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Vitamin K and Exercise Benefits

Vitamin K and Exercise

  • When you exercise or move, the organ systems of your body coordinate a response in the bio physiology of movement.
  • These organ systems include cardiovascular, lungs, bones, muscle, and mitochondria.
  • Research indicates that vitamin K is an omni vitamin that is critical to the functioning of each these systems.
  • Research indicates that a vitamin K deficiency is associated with the risk of disease and impaired functioning that would interfere with exercising.
  • The direct role of vitamin K in improving exercise is being explored, with recent work showing that K intake significantly raised VO2 max in just 8 weeks.
  • Overall, vitamin K can be your best training partner to improve your physical performance!

Physical activity, whether it be dancing in a ballroom, playing in a park, swimming in a lake, or following an exercise routine, is what the body is designed for, and what the body needs.

There are concerns worldwide that the popular lifestyles of inactivity, electronics, and a poor diet are contributing to disease and a decline in health.  This paper will review the major systems of the body that are engaged with physical activity and movement, and present research on the significant role of vitamin K in supporting and improving the biophysiology of movement.

This research applies to everyone, from an elderly walker to an elite athlete, with vitamin K being your best fitness partner.

What Happens When You Move
Physical movement, ranging from chair aerobics to training for the Olympics, requires key organ systems of the body to respond in coordination.  These organ systems include the lungs, cardiovascular system, bones, and muscles, as well as the mitochondria which produce the energy needed to power the body in movement.

When you begin to exercise, the first thing you probably notice is your heart and breathing rates increase. Your muscles need oxygen, so your heart will begin to beat faster to pump more blood to your muscles, while your stomach will slow down because digestion is not the body’s main priority anymore.

Increasing your activity level will cause an increase in your respiration rate.  Your body may need up to 15 times more oxygen when you exercise, so you start to breathe faster and heavier.  Your breathing rate will increase until the muscles surrounding the lungs just can’t move any faster.

As you exercise, the large muscles in your arms and legs squeeze the veins running through them, raising blood pressure and pumping blood back to your heart. Muscle and coronary blood flow increase, while cerebral blood flow is maintained as a constant.

The blood pumping through your system will also raise your core temperature and increase blood flow to the skin to dissipate body heat.  Your two million sweat glands can produce 1.4 liters of sweat per hour.  The evaporation of sweat is a major pathway for heat loss and further heat is lost in the air when exhaling. 

Your muscles need energy for your workout, so your body burns fats and carbohydrates in a series of cellular chemical reactions that produce heat.  Mitochondria in your cells use oxygen to break down sugars to charge up ATP molecules; ATP refers to adenosine triphosphate which is an energy molecule in your cells.  When your body breaks down glucose, carbon dioxide gas is produced, which you exhale.

Exercise calls on all the major organ systems of the body to become engaged and perform to the capacity they have attained (Lee et al, 2022). We will review the most central systems, their contribution to exercise, and an overview of research on the ways that vitamin K intake helps these organ systems function better and enhance the outcomes of exercise.

Vitamin K
The term vitamin K refers to a family of fat-soluble vitamins, which the body stores in fat tissue and the liver.  Vitamin K is best known for its role in helping the coagulation system to ensure that blood clots or coagulates properly. The "K" comes from its German name, Koagulations vitamin. 

Through further research, it became clear that vitamin K had a significant impact well beyond the coagulation system.  Research has elucidated a host of proteins in tissues throughout the body that depend on vitamin K, beyond the coagulation system.  All these proteins are known as Vitamin K Dependent Proteins or VKDP.  Research has steadily discovered more of these proteins and their importance in health. Some of the most research proteins include matrix Gla protein (MGP), growth arrest-specific protein 6 (Gas6), osteocalcin (OC), and Gla-rich protein (GRP) (Wen et al, 2018).  Through these proteins, vitamin K acts on almost every system in the body, and thus has a tremendous impact on movement and fitness. (Danziger, 2008; Willems et al, 2014; Beulens et al, 2013; Popa et al, 2021).

Vitamin K also engages with these systems via signaling pathways and triggering genetic expression, but there is much less research available as it relates to movement so this discussion will primarily focus on the proteins that are activated (Gordeladze et al, 2017; Zhang et al, 2019; Su et al, 2021; Jadhav et al, 2022; Rønning et al, 2018). 

Vitamin K1 and vitamin K2 are the two main forms of vitamin K, differing in their chemical structure (Shearer & Newman, 20). Vitamin K1 is mostly found in green plants, like spinach, broccoli, lettuces or parsley, and accounts for more than 50% of the dietary intake of vitamin K (Booth, 2012). Vitamin K2 is found in fermented products where bacteria are part of the production process, such as natto, hard cheeses, egg yolk, meat, and dairy products, etc, and it can also be produced by the gut bacteria (Bentley & Meganathan, 1982; Shearer & Newman, 2017; Shearer et al, 2012; Marles et al, 2017; Vermeer et al, 2018).

Both Vitamin K1 and K2 are an essential cofactor for the γ-glutamyl carboxylase (GGCX) an enzyme that converts glutamic acid (Glu) residues into γ-carboxyglutamic acid (Gla) in the Gla protein family (Azuma et al, 2014). The process of converting Glu to Gla is known as carboxylation.  This is a very important transformation, enabling these proteins to bind calcium and function normally (Proudfoot et al, 1998; Kapoor et al, 2021). GGCX is expressed in different tissues, including the liver, brain, heart, kidney, lung, bones, pancreas and skeletal muscle (Wu et al, 1997; Berkner & Runge, 2022; Yan et al, 2023). Research has shown that intake of vitamin K may need to be greater than the recommended daily allowance to carboxylate these proteins sufficiently (Nakamura et al, 2014).

HEART-CARDIOVASCULAR SYSTEM

As in life, your heart plays a fundamental role in physical activity and exercise.

Your heart and the many blood vessels in your body make up your cardiovascular system. The purpose of the cardiovascular system is to circulate oxygen and nutrients through your whole body via an intricate network of blood vessels.  This network also removes the things your body doesn’t need, such as carbon dioxide.  The system also assists with thermoregulation and helps to eliminate heat.

Measures of the cardiovascular system include stroke volume, cardiac output, systolic blood pressure and mean arterial pressure.  Stroke volume is the volume of blood pumped out of the left ventricle of the heart during each contraction.  Cardiac output is the amount of blood the heart pumps in one minute.  Systolic blood pressure is a measure of the pressure your blood is exerting against your artery walls when the heart contracts.  The mean arterial pressure is the average arterial pressure during a single cardiac cycle. 

The fitness of the cardiovascular system is defined by the body’s ability to deliver oxygen to your muscles.  The lungs take in oxygen from the air we breathe where it gets perfused into the blood stream, the heart and blood vessels deliver it into the working muscles, and the skeletal muscles utilize that oxygen to execute muscular contractions. 

Exercising and physical activity cause the cardiovascular system to adapt and improve, promoting cardiovascular fitness (Pinckard et al, 2019). During exercise, two major adjustments occur. First, cardiac output from the heart increases, as cardiac output is a major determinant of oxygen uptake.  The increased cardiac output leads to an increase in heart rate and stroke volume, as well as an increase in oxygen consumption.  Heart rate can increase threefold, and stroke volume can increase by about 30 to 40%.  During strenuous exercise, heart rate and stroke volume can increase to about 90% of their maximum values. When maximum stroke volume is increased, the heart can work more efficiently at a given pulse rate and increase the amount of blood that goes out to the rest of the body and muscles.

The second adjustment is blood flow from inactive organs and tissues is redistributed to active skeletal muscle. At rest, muscles receive approximately 20% of the total blood flow, but during exercise, the blood flow to muscles increases to 80-85%. During maximal exercise, almost all the available oxygen in the blood is extracted by skeletal muscle. (Beere et al, 1999; Joyner & Casey, 2015).  With repeated exercise, new blood vessels form in muscle, increasing skeletal muscle blood supply.  The increased vascular density coupled with greater dilation capacity, leads to enhanced oxygen extraction and perfusion capability, an important component of fitness (Sun et al, 1994; Naik et al, 1999; Huonker et al, 2003; Saunders & Tschakovsky, 2004; Hoier et al, 2014; Joyner & Casey, 2015; Laughlin et al, 2017). 

Regular exercise leads to a decreased resting heart rate, lower blood pressure, and increased cardiac muscle mass (Platt et al, 2015; Vega et al, 2017; Che & Li, 2017).  The more you exercise, the more efficient the heart becomes at this process, so you can work out harder and longer (Laughlin et al, 2012; Fontana, 2018; Duncker & Bache, 2008). 

Cardiorespiratory fitness (CRF), is often referred to as (VO2max). V02 max is defined as the maximum rate of oxygen that can be delivered to and used by the working muscles, aerobic capacity.  The more oxygen your body absorbs per minute, the higher your VO2 Max, and the more fit a person is (Green & Askew, 1985; Poole & Jones, 1985; Burtscher et al, 2019; Valenzuela et al, 2020).  V02 max reflects the entire oxygen transport system – the lungs, cardiovascular, and active muscles- which transport and utilize the oxygen in the blood stream. 

VO2 max is measured in milliliters of oxygen used in one minute per kilogram of body weight (mL/kg/min). It is based on the premise that the more oxygen athletes consume during high-level exercise, the more the body will generate energy in the cells. 

VO2max values can vary greatly between individuals, with untrained individuals typically having a range of 25-45 ml/kg/min while elite endurance athletes have values in the 80s or even 90s.  Males tend to have higher values than females.  After 30 years of age, VO2 max progressively decreases with age at a rate of about 10% per decade (Jansson & Kaijser, 1987; Simon et al, 1986; Levine, 2008), though appropriate training can slow the pace of decline (Haugen et al, 2018; Rønnestad et al, 1985; Weibel & Hoppeler, 200). 

Aging can impact heart functioning, leading to a decline in maximal heart rate and in V02 max levels.  Cardiovascular disease, such as the stiffening of arteries, or heart disease, can negatively affect blood flow and oxygen delivery to skeletal muscles (Poole et al, 2002; Burtscher et al, 2022).  Any intervention that mitigates the effect of aging, such as vitamin K is important. 

Cardiac function is a major determinant of peak exercise performance in addition to pulmonary and skeletal muscle function. Exercise performance is affected by many cardiac disease states (Kennel et al, 2015) Additionally, reduced cardiac output over time, can affect the peripheral vasculature as well as the skeletal muscle, leading to a decreased exercise capacity (Duscha et al, 2008; Gosker et al, 2000). 

Research has documented the impact of impaired cardiac function on exercise.  Folks diagnosed with hypertension and high blood pressure showed impaired skeletal muscle oxygenation. Consequently, during submaximal exercise their blood pressure increased 2-fold to achieve the similar muscle oxygenation that healthy folks could achieve (Dipla et al, 2017).  A study of diabetic subjects showed femoral arterial blood flow was caused by impaired vascular function and reduced tissue perfusion, which limited oxygen extraction to the muscle (LaLande et al, 2008). Studies of patients with heart failure have found under-perfusion to the skeletal. Muscle and lactic acidosis (Duscha et al, 2008; Gosker et al, 2000; Saltin & Calbet, 2006). 

Peripheral artery disease (PAD) is a common manifestation of atherosclerosis in the lower limbs.  Atherosclerotic plaques tend to develop in the peripheral arteries, increasing vascular resistance and limiting blood flow as well as the delivery of oxygen and nutrients to tissue, and perfusion in skeletal muscles.  The vasculature is unable to quickly respond to exercise (Kravitz & Dalleck, 2002; Haykowsky et al, 2012; Englund et al, 2013). Patients with Peripheral Arterial Disease (PAD) with no prior revascularization procedures were recruited from the Baltimore Veterans Affairs Medical Center and compared with control patients without PAD. Control subjects demonstrated a more rapid time to peak perfusion (TTP) and an increase in peak perfusion after exercise.  Patients with PAD showed no significant exercise-induced changes in perfusion and PEAK, indicating that the PAD impaired their response (Kundi et al, 2017). 

Vitamin K and the Heart

Decades of research have shown that vitamin K supports heart health and functioning and could be an important intervention for exercise success.  Vitamin K helps prevent calcification, it keeps your vascular system from stiffening, it is anti-inflammatory, and it helps create maximum heart output (Crintea et al, 2021).

--Vascular calcification 
Vascular calcification is a pathological process and is manifested by deposits of hydroxyapatite, a form of calcium, in the blood vessel walls (Wasilewski et al, 2019).  Ninety‐nine percent of bodily calcium is stored in bone, with the remaining 1% circulating in the blood, muscle, and other tissues (Weaver, 2012). Calcium storage in the bone occurs with the presence of vitamin K2 and the protein osteocalcin.  Low levels of vitamin K2 can cause disruption in the binding between calcium and osteocalcin, leading to the buildup of calcium to other tissues such as arteries (Maresz, 2015).

This calcification is cumulative and can lead to an increased risk of hypertension, atherosclerosis, ischemia, myocardial infarction, and other forms of functional decline in the cardiovascular system.  It used to be that vascular calcification was viewed as a standard part of the pathological aging process, but now is understood to be an active and regulated process that can be managed and improved with adequate vitamin K intake (Roumeliotis et a, 2019).

Ample evidence from animal and clinical studies has shown that low levels of vitamin K (suggesting low intake) may be associated with vascular calcification and an elevated risk of cardiovascular diseases (Mozos et al, 2017; Jaminion et al, 2020; Shioi et al, 2020; Dalmeijer et al, 2013). 

Several studies demonstrated that higher dietary consumption of vitamin K2, significantly reduced the incidence of calcification and coronary heart disease (Geleijnse et al 2004; Gast et al, 2009). After monitoring 2987 participants during a median follow-up time of 11 years, intake of K2 was associated with a significantly lower risk of heart disease (Haugsgjerd et al, 2020), and a slowed progression of preexisting coronary artery calcification (CAC), in asymptomatic older men and women (Shea et al, 2009).

Cardiovascular tissues contain several key proteins that are dependent upon vitamin K to be active.  Some of these proteins include, Matrix Gla Protein (MGP), Gla rich protein (GRP), and Growth arrest-specific protein-6 (Gas6).  Matrix Gla protein is the most influential natural inhibitor of all types of calcification in the body and is closely associated with mortality, and cardiovascular disease (Price et al, 1983; Akbari & Rasouli‐Ghahroudi, 2018; Nishimoto & Nishimoto, 2005). Upon activation, MGP binds calcium, thereby inhibiting the calcification process, removing it from circulation and leading it to the bones (Goiko et al, 2013; Cui et al, 2018; Jaminion et al, 2020).

When not activated by vitamin K, MGP is associated with (peripheral) vascular calcification and carotid femoral/aortic pulse wave velocity, suggesting that it is a risk biomarker associated with mortality and the severity of vascular calcification and cardiac function (Schurgers et al, 2010; Ueland et al, 2010; Schlieper et al, 2011; Ueland et al, 2011; Dalmeijer et al, 2012; Rennenberg et al, 2010; Dalmeijer et al, 2013; Liu et al, 2015; Griffin et al, 2019; Wei et al, 2016;  Roumeliotis et al, 2019). 

Research shows that levels of activated MGP increase after improved vitamin K intake, in a dose dependent manner, meaning the more vitamin K taken, the higher levels of active MGP are found in the body, available to help reduce calcification (Westenfeld et al, 2012; Caluwe et al, 2014).

Additionally, Vitamin K modulates the Gas6 pathway which also inhibits the vascular calcification process (Jadhav et al, 2022, Jiang et al, 2016). Gas6 has been shown to suppress vascular calcification and reduce coronary heart disease (Beulens et al, 2009; Geleijnse et al, 2004; Vossen et al, 2015; Qiu et al, 2017).

--Arterial Elasticity
Pulse wave velocity (PWV) is the velocity at which the blood pressure pulse propagates through the circulatory system.  It is used as a measure of arterial stiffness and is a predictor of cardiovascular risk.  The stiffer and harder the blood vessel walls, the wider the pulse pressure and the more the heart is working to pump blood into the arteries (Seals et al, 2006).  A study of patients with hypertension found that low intakes of vitamin K led to lower muscle mass and increased large artery stiffness (Vidula et al, 2022).

Vitamin K has been shown to significantly delay the onset of arterial stiffness in postmenopausal women (Braam et al, 2004).  In another study, patients who received MK7 had better pulse wave velocities than those who received placebos (Knapen et al, 2015).  And those with more stiffness have high levels of uncarboxylated MGP, a marker of K deficiency indicating that vitamin K intake leads to better arterial function (Pivin et al, 2015; Roumeliotis et al, 2019; Wei et al, 2019).

The vascular system is lined with smooth muscle cells.  Smooth muscle cells (SMCs) provide the main support for the structure of the vessel wall and maintain intravascular pressure and tissue perfusion (Wang et al, 2015).  Vitamin K promotes vascular smooth muscle differentiation, which may be associated with a better perfusion of muscle tissue (Chatrou et al, 2011).  

--Anti-inflammatory
Vascular calcification is also regarded as a chronic inflammatory state mediated by the NF-кB signaling pathway.  NF-κB is a transcription factor that plays a crucial role with inflammation and the immune response.  A high vitamin K status exerts anti-inflammatory effects and prevents calcification through antagonizing NF-кB signaling (Shioi et al, 2020). 

Interleukins are cell proteins that defend the body and ensure that our immune system is responsive.  High levels of IL-6 are strongly associated with chronic inflammation and most pro-inflammatory diseases, including obesity, arthritis, cancers. A lab study showed that all the vitamin K forms K1, MK3, MK4, and MK7 were anti-inflammatory and suppressed IL-6, with MK4 having the most impact (Ohsaki et al, 2010).  

The Multi-Ethnic Study of Atherosclerosis (MESA), showed that blood levels of vitamin K1 were inversely associated with inflammatory markers namely IL-6 and C-Reactive Protein (Shea et al, 2014). A cohort analysis of 1163 older adults in the Health ABC study, found that those with lower circulating levels of K1 at baseline, also had higher circulating IL-6 levels, further supporting the anti-inflammatory effect of vitamin K at a systemic level (Shea et al, 2017). 

Vitamin K is required for the effective function of a range of proteins (Shearer & Okano, 2018) involved with inflammation and neuromuscular function (Harshman & Shea, 2016; Lees et al, 2019; Aoi et al, 2004; Paulsen et al, 2012).  For these reasons, a pilot study has begun to determine whether vitamin K2 supplementation can modulate responses to exercise, and accelerate recovery in young and older adults (Lithgow et al, 2022).  

--Maximal Cardiac Output

A recent study showed a powerful effect of MK7 on heart output during exercise in active athletes.  In a recent randomized controlled trial, MK7 was given to subjects during an 8- week period, while they maintained their typical exercise habits.  They found that MK7 intake was associated with a 12% increase in maximal cardiac output, using a graded cycle ergometer test.  This was the first study to report potential of vitamin K in active individuals. 

The major finding was that cardiac output rose by a very significant 12% for the athletes receiving vitamin K2.  Cardiac output was defined as the maximum amount of blood (and therefore oxygen) that the heart can pump around the body each minute.  This increase translates to an increase in the maximum amount of blood and oxygen available to exercising muscles, which should improve endurance.  Research on elite runners and cyclists have confirmed that high cardiac outputs are associated with high levels of endurance performance (McFarlin et al, 2017). 

RESPIRATION SYSTEM – Lungs1
Lungs are part of the respiratory system, a group of organs and tissues that work together to help you breathe.  The respiratory system's main job is to move fresh air into your body while removing carbon dioxide, and it includes the nose, mouth, throat, voice box, windpipe, and lungs.  The architecture of the lung includes its vasculature, conducting airways, and airspace compartments which include the alveoli.  Alveoli are air sacs in the lungs located at the end of the respiratory “tree branches.” 

Breathing is the movement of air into and out of the lungs with each expansion and contraction of the lung.  The air we breathe contains oxygen and other gases. When we inhale, the air travels to the alveoli, where oxygen and carbon dioxide are exchanged.  Once absorbed in the lungs, oxygen is pushed to your heart, which pumps it through your body, supplying oxygen to the body’s cells. Every cell in your body needs oxygen to live. Breathing is the first stage for supplying oxygen to the body’s cells.

At each cell in your body, oxygen is exchanged for a waste gas called carbon dioxide. Carbon dioxide is made in our bodies as the cells do their jobs.  Too much carbon dioxide can result in damage to muscles or other body parts, so it must be removed. Your bloodstream carries this waste gas back to the lungs where it is removed from the bloodstream and then exhaled. Your lungs and respiratory system automatically perform this vital process.

When you exercise and your muscles work harder, your body uses more oxygen and produces more carbon dioxide. To cope with this extra demand, your breathing must increase from a resting rate of about 15 times a minute (12 liters of air) up to about 40–60 times a minute (100 liters of air) to supply the increased amount of energy the muscles need to contract while exercising. Your heart rate and circulation also speed up to take the oxygen to the muscles so that they can keep moving. 

An important tissue in lungs is elastin.  Elastin is a unique protein that provides elasticity and resilience to dynamic tissues, such as arteries and lungs (Davidson, 1992; Mariani et al, 1997; Noakes, 1996; Luo et al, 2018).  The elastin protein is roughly 1,000 times more flexible than the rigid protein, collagen. Elastin confers resilience upon structures that undergo repetitive stress, enabling them to retain their expand and contract functionality and tensile strength (Mercer & Crapo, 1990; Mithieux & Weiss, 2006; Mecham, 2018; Jesperson et al, 2023; Kristensen & Karsdal, 2016; Cocciolone et al, 2018). 

Calcification and degradation are two pathologic processes that impair elastin’s functioning. Elastin has high affinity for calcium, and the calcium content of elastin fibers increases during aging (Piscaer et al, 2017), leading to degradation (Luo et al, 1997; Mitheaux et al, 2005; Janssen & Vermeer, 2017). 

Lungs are to breath what joints are to mobility.  Without elastin, lungs would be unable to carry out their duties effectively.  Every time you breathe in and out, whether you are exercising, sleeping, or simply flowing through your day, the elastin in your lungs is in full engagement (Wendel et al, 1999). 

VO2 Max is common measure of aerobic capacity.  VO2 max is measured in milliliters of oxygen used in one minute per kilogram of body weight (mL/kg/min). It is based on the premise that the more oxygen athletes consume during high-level exercise, the more the body will generate energy in the cells.

VO2max values can vary greatly between individuals, with untrained individuals typically having a range of 25-45 ml/kg/min while elite endurance athletes have values in the 80s or even 90s.  Males tend to have higher values than females.  After 30 years of age, VO2 max progressively decreases with age at a rate of about 10% per decade  (Jansson & Kaijser, 1987; Levine, 2008; Simon et al, 1986),  while longitudinal studies suggest that VO2max decline may accelerate after ages 40–50 years, though appropriate training can slow the pace of decline (Fleg et al, 2005; McGavock et al, 2009; Haugen et al, 2018; Rønnestad et al, 1985; Weibel & Hoppeler, 2005).

The decline in aerobic capacity is likely related to an increase in the stiffness of the pulmonary vasculature. In principle, stiffer elastin fibers contribute to the increase in vascular stiffness that comes with age. These changes in pulmonary vascular stiffness modify lung capacity in older individuals (Gonza et al, 1974; Harris & Heath, 1965; Hosoda et al, 1984; Mackay et al, 1978; Plank et al, 1980). 

-VITAMIN K AND THE LUNGS
Vitamin K supports the lungs in their most basic function – to move – as they expand and contract with every breath.  Vitamin K activates protein in elastin which maximizes the function of lung tissue and lung vasculature during exercise and movement.  Without vitamin K, the elastin in the lungs is less flexible, and exercise capacity would be dramatically impaired.

Elastin is an important component of both lungs and arteries, and, although the arrangement of elastic fibers is different for each type of tissue (Mithieux et al, 2005), the elastin protein itself has comparable chemical properties. It is therefore expected that the research on the role of matrix Gla protein (Schurgers et al, 2013) in the vasculature system would also apply to lung tissue.

Matrix Gla protein (MGP) is vitamin K-dependent and a potent inhibitor of soft tissue calcification, and elastin calcification specifically (Fraser & Price, 1988; Luo et al, 1997; Schurgers et al, 2013).  MGP inhibits elastic fiber calcification (Fraser et al, 1988) and prevents fiber degradation. A rising calcium content in elastin fibers stimulates MGP synthesis to prevent further calcium precipitation within the elastin fibers (Price et al, 2001).

The ‘Vitamin K deficit and ‘elastolysis theory’ posits that elastin degradation causes vitamin K to become deficient and implies that vitamin K supplementation could be preventing elastin degradation (Schurgers et al, 2013; Piscaer et al, 2019).

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes obstructed airflow from the lungs.  COPD is characterized by accelerated elastic fiber degradation (Vogelmeier et al, 2017; Lee et al, 2007). Elastin degradation is partially regulated and inhibited by Matrix Gla Protein (MGP), via a vitamin K-dependent pathway (Schurgers et al, 2013).  Indeed, high dp-ucMGP levels (representing vitamin K deficiency) were associated with increased elastin degradation rate in four independent cohorts, including two cohorts of COPD patients (Piscaer et al, 2018; Dofferhoff et al, 2021; Piscaer et al, 2017).  A follow up study demonstrated that patients with COPD had a reduced vitamin K status, where the lower the status of vitamin K was associated with a greater rate of elastin degradation. The results suggested a potential role of vitamin K in COPD pathogenesis (Piscaer et al, 2019).

Research during the pandemic indicated that uncarboxylated MGP was severely elevated in hospitalized Covid-19 patients. Impaired MGP activation was associated with poor outcome and accelerated elastic fiber degradation in patients with Covid-19 (Dofferhoff et al, 2021). 

Another study examined the association between low vitamin K status and lung function in the general population of Denmark.  They found that low vitamin K status was associated with lower ventilatory capacity.  The Danish study of Functional Disorders (DanFunD) cohort was a random sample of the general adult population comprising men and women born in Denmark (Dantoft et al, 2017). Participants underwent health examinations. The results showed that lower vitamin K status was associated with a lower ventilatory capacity and a higher risk of self-reported asthma, COPD, and wheezing (Jesperson et al, 2023). 

Lung functioning are a crucial part of physical movement and exercise.  The research indicates that the health of your lungs depends on an adequate intake of vitamin K, to make your lung tissue pliable and able to best take in the oxygen that will power your muscles and body.

BONES
Bone can be described as the ultimate smart composite material, which enables it to fulfill many essential physiological functions. Bone is primarily made up of two components, an organic part comprised of collagenous and non-collagenous proteins (30%) and cells, and a mineral component of hydroxyapatite (70%) composed primarily of calcium and phosphate (Boskey, 2013). These components allow bone to act as a scaffold for muscle and other organs, protecting the organs from injury while forming a load-bearing framework that allows physical activity to take place (Russo, 2009). 

The organic component of bone includes at least two vitamin K‐dependent Gla proteins; osteocalcin and matrix Gla protein (MGP) (Azuma et al, 2014; Zhou et al, 2021).  These proteins need vitamin K as a cofactor to allow them to bind to calcium ions in the bone matrix (Shearer et al, 2012).  It is the collagen proteins that give bones their flexibility, and the hydroxyapatite that gives them strength and rigidity. This unique combination of rigidity and flexibility allows bones to withstand an extensive range of strain and weight, making it in some cases, as strong as steel and as light as aluminum.

Bone also functions as an important mineral reserve.  Hydroxyapatite is mainly composed of calcium, phosphorus, magnesium, and other minerals in lesser amounts (Bronner, 2001; Murshed, 2017; Whyte, 2017).  Calcium is an important element in the body.  Its main job is to build strong bones and teeth, which contain 99% of the body's calcium.  Calcium is also necessary to propagate electrical signals in the nervous system, support clotting factors, and enable muscle contraction, including the beat of your heart, among other vital functions.  The bone mineral reserve also serves to maintain the calcium content in our blood, as well as make good use of ingested calcium (Heaney, 2006).

Important bone building occurs during childhood, through adolescence and early adulthood, up to the mid-20s.  In the first decades of life, physical activity and appropriate nutrition help your skeleton achieve greater peak bone mass and density.  As the child ages, bone modeling occurs to accommodate the growth of bone and to adapt the skeleton to mechanical strain.  If a child is inactive and/or eats a nutrient deficient diet, they are at high risk for low bone mass and bone weakness (Arfat et al, 2014; Klein-Nulend et al, 2013; Robling & Turner, 2009; Weaver et al, 2016).

For most people, bone mass peaks around the age of 35. At around age 40, bone density begins to decrease. In women, the speed of bone loss accelerates with the onset of menopause.  If adequate bone was not built during childhood, a person is at risk for weaker bones in adulthood.

Bone is a dynamic tissue that interacts with and responds to its environment, such as physical activity and exercise.  Physical activity creates load and forces on bones through the contractile activity of muscles and through ground reaction forces (Lanyon et al, 1975; Usui et al, 2003).  (Ground reaction forces are exerted by the ground on the body as contact is made, and the force accelerates with movement.)  When your muscles pull on your bones, it responds during the moment, while also starting a cascade of biochemical signals that will begin to strengthen those areas of the bone (Goodman et al, 2015).  The harder the muscles tug, the more your body renews and strengthens those bones through increased calcium deposits; accordingly, bones become denser and stronger.

These physical forces result in maintaining or gaining of bone mass, and drive adaptation of bone structure. Bone traits, such as density, strength and architecture, respond and adapt to help the skeleton to cope with the loading environment while preventing injuries.  (Sharkey et al, 1995, Lu et al, 1997; Burr, 1997).

For example, the racket arm of a tennis player has greater bone mass than the non-racket arm (Haapasalo et al, 2000; Ireland et al, 2017).  Conversely, 6-months of spaceflight results in a 10% loss in the bone density of astronauts living under zero gravity conditions, where gravitational mechanical loading and, therefore, ground-reaction forces are missing (Sibonga, 2013). 

Once we reach the age of about 25, physical activity alone will no longer increase overall bone mass dramatically.  In adults, bone density may increase 1-2%, but this increase occurs only around the area of the skeleton that is stressed by specific exercise.  This improved density will be lost if the loading exercise is not continued (Nilsson et al, 2009; Ducher et al, 2005; Greenhill, 2016).

--Bone Remodeling
Bone constantly destroys and regenerates itself through a process termed remodeling. To fulfil this function, bone hosts two functionally antagonistic cell populations: osteoclasts, which break down bone tissue and resorb mineralized bone matrix; and osteoblasts, which deposit new matrix, building bone that eventually becomes mineralized. (Hadjidakis & Androulakis, 2006; Baron & Kneissel, 2013; Hiam et al, 2021).

This succession of destruction and formation occurs constantly throughout the skeleton.  It takes 3-4 months for one remodeling cycle to complete the sequence of bone resorption, formation, and mineralization, and a minimum of 6-8 months to achieve a new steady-state bone mass that is measurable (Ducy, 2011). 

While bone modeling occurs primarily in childhood, bone remodeling happens mainly during adulthood to remove microdamaged and old bone, adapt bone tissue to mechanical loading, and maintain the strength and integrity of the skeleton (Sims & Martin, 2014).

--Inactivity
Exercise and good nutrition are important for building strong bones when we are younger, and they are both essential for maintaining bone strength when we are older.  Altering either element can reduce bone quality and strength.

A lack of exercise results in a decrease of bone mass and density which leads to a reduction in bone strength.  Bones become brittle and prone to fractures, even from normal movement (Heaney et al, 2000; Suominen, 2006; Cabahug-Zuckerman et al, 2016).  A lack of sufficient intake of the nutrient vitamin K in the diet means the proteins throughout the body that depend on vitamin K are not activated, impairing their function.  Current dietary guidelines in the US are primarily based on coagulation needs only and are not enough to induce complete activation of all the proteins that depend on vitamin K (DiNicolantonio et al, 2015). 

-Osteopenia is the term for the early stage of weakening bones.  If no action is taken and bone density continues to drop, osteoporosis develops. Osteoporosis means bone full of pores or holes. Osteoporosis is a chronic disease characterizes by weak bone tissue, which leads to a significant increase in the risk of bone fragility and fracture (Baccaro et al, 2015).

Recent studies proved that bone cells have endocrine functions. They can synthesize and secrete a variety of bioactive substances, such as proteins, polypeptides, cytokines, inflammatory factors, adipokines, and exosomes. These bioactive substances help regulate bone remodeling.  Additionally, these substances can be released into the circulation and target other organs, such as the pancreas, thereby affecting the energy metabolism of the whole body (Andrukhova et al, 2016; Cai et al, 2017; Karsenty, 2017; Lu et al, 2020; Anaraki et al, 2015; Shao et al, 2015; Matsouka et al, 2014; Shimada et al, 2004).

One of the key players in bone endocrinology is osteocalcin, which is released by osteoblasts in the skeleton, and which has been found to control glucose metabolism, mineral homeostasis, brain development, male fertility, and exercise capacity (Grueter et al, 2012; Lee et al, 2007).  It was initially found to promote the proliferation of pancreatic β-cells and insulin secretion and later, its other functions in energy regulation were established (Karsenty, 2006; Gupte et al, 2014;, Mizokami et al, 2013; Otani et al, 2015; Kajimura et al, 2013; Lecka-Czernik, 2017; Ferron et al, 2020).

-VITAMIN K AND BONES
There is a wealth of research on the importance of vitamin K and bone health, and how K supports physical activity and fitness.  Physical movement and exercise require your bones to be strong and solid, so they can power movement, and not suffer fractures of any kind. Bone diseases such as osteopenia, osteoporosis and arthritis impact bone function and interfere with exercise.  The research shows that vitamin K helps to preserve bone health in multiple ways.

There are many vitamin K dependent proteins in the bone, including osteocalcin (OC), matrix Gla protein (MGP), gas 6, periostin, and protein S (Fusaro, et al, 2017). Vitamin K also regulates the transcription of osteoblast markers, the formation of osteoclasts, and bone resorption. 

--Osteocalcin
Osteocalcin is the most abundant non-collagenous protein in the bone matrix. It is synthesized by osteoblasts and is released to help take calcium from the blood circulation and bind it to the bone matrix, promoting mineralization, which in turn makes the skeleton stronger and less susceptible to fracture (Hoang et al, 2003).  However, the newly made osteocalcin is inactive, and it needs vitamin K to become fully activated and carboxylated, which is noted as cOC (Hauschka, 1986; Hauschka et al, 1989).  Inactive or uncarboxylated osteocalcin is noted as ucOC.  That requirement alone makes vitamin K a major player in bone health, and subsequently a major player for optimal fitness and physical activity. 

During bone resorption, uncarboxylated osteocalcin is released into the blood, and is used as a biomarker for bone metabolism and turnover (Beulens et al, 2013).  Many studies found that low concentrations of vitamin K1 in the blood are associated with high levels of undercarboxylated osteocalcin (ucOC) (Fusaro et al, 2016).  Uncarboxylated osteocalcin can also act as a hormone and participates in the insulin cycle, reaching pancreatic beta cells to increase their proliferation and enhance the production and release of insulin. In turn, insulin stimulates osteocalcin production by osteoblasts and subsequently triggers its release through bone resorption  (Gundberg et al, 2002; Lee et al, 2007; Levinger et al, 2017; Lin et al, 2018; Michelsen et al, 2013; Hiam et al, 2019; Lin et al, 2020). The carboxylated form of osteocalcin (cOC) is involved in bone mineralization (Ivaska et al, 2004), and elevated cOC is positively correlated with bone formation and osteoblast number (Neve et al, 2013; Levinger et al, 2014).

Research shows that a high intake of MK4 daily (45 mg) activated osteocalcin, and bone density increased, indicating a correlation between K2 and bone health (Ozuru et al, 2002).  Lab studies showed increased osteocalcin production after exposure of osteoblasts to Vitamin K2 (Matsunaga et al, 1999; Koshihara et al, 2003) and increased expression of genes that form bone (Akbari & Rasouli‐Ghahroud, 2018).

Exercise is sensed by bone cells.  The mechanical stress on the skeleton initiates strains that are recognized by bone cells, and they start a cascade of events that lead to stronger bone.  Their response can be measured by markers of bone turnover, such as osteocalcin, which increases during exercise (Lanyon, 1984; Banfi et al, 2010; Ferron et al, 2010; Vasikaran S et al, 2011; Brotto & Johnson, 2014; Levinger et al, 2016; Smith et al, 2021; Komori, 2022; Hiam et al, 2019; Adami et al, 2008; Rahimi et al, 2020; Chowdhury et al, 2020; Rahimi et al, 2021).  This effect is found in different age groups and by sex (Lin et al, 2012; Kim et al, 2016; Rämson et al, 2012). 

--Vitamin K contributes to strong bones  
Studies of people around the world have shown that vitamin K improves the markers of bone building and bone mineral density (BMD). A Korean study showed that administering 15 mg of vitamin K2 (MK4) three times daily, for six months to postmenopausal women significantly increased the bone density of the lumbar spine while increasing the level of cOC (Je et al, 2011;  Shiraki et al, 2000). Taking 1.5 milligrams of MK4 daily increased the serum levels of cOC in postmenopausal Norwegian women compared to a group who received a placebo (Emaus et al, 2010).  Another study showed that subjects given 200 micrograms of MK7 had an increase in cOC, indicating better bone quality for postmenopausal women, while those who were not given MK7 had an increase in ucOC (reflecting a deficiency) (Inaba et al, 2015). Post-menopausal Japanese women with osteoporosis taking MK4 for 6-12 months showed significant improvement of vertebral BMD (Koitaya et al, 2014).  Postmenopausal Syrian women, without estrogen replacement therapy, had a positive correlation of their K1 levels with with lumbar spine bone mineral density, indicating that measures of K1 might be a valuable diagnostic tool (Jaghsi et al, 2018).

Multiple studies were conducted to evaluate the effect of vitamin K on bone mineral density. A study in the Netherlands of postmenopausal women showed that taking 45 mg/day of MK4 for three years prevented loss of hip bone strength, whereas the group who did not receive MK4 had a significant loss of bone (Knapen et al, 2007).  Huang (et al, 2015) performed a meta-analysis of 19 clinical trials, which included 6759 participants.  The data supported the role of vitamin K2 in the maintenance and improvement of vertebral BMD and the prevention of fractures in postmenopausal women with osteoporosis. Another review of found that vitamin K2 is osteoprotective (Akbari et al, 2018). Another review involving a total of 6,425 subjects found a significant improvement in lumbar spine bone mineral density when given vitamin K2, and a significant reduction in fracture incidence.  Another meta-analysis showed that vitamin K2 increased the level of cOC, and reduced the fracture incidence (Ma et al, 2022).  Sato and colleagues reviewed the literature on MK7 and conclude its higher bioavailability and longer half-life increase bone mineral density and strength (Sato et al, 2020).

Collagen is an important component for bone that builds strength and flexibility and occupies more than half the volume of bones.  It is responsible for matrix production, the material on which calcium and other minerals accumulate and is critical for bone formation. Research shows that MK-4 increases collagen accumulation (Ichikawa et al, 2006) and MK-7 increased collagen production (Sato, 2012).

Glucocorticoids are often given for inflammation; however, they lead to a decrease in bone density and an increase in fracture risk.  In animal models, even with glucocorticoid damage, K2 still showed an osteoprotective effect on osteoblasts, and promoted bone healing in osteoporotic rat models (Iwamoto et al, 2010; Zhang et al, 2017).

--Vitamin K reduces the risk of fractures 
Exercise and physical activity require weight and load to be placed on bones.  Research shows that both vitamin K1 and K2 reduce the risk of fractures and microfractures.

Low dietary vitamin K consumption and a high proportion of ucOC are independent risk factors for bone fractures in mature populations (Szulc et al, 1993; Seibel et al, 1997; Vergnaud et al, 1997; Fusaro et al, 2020; Shiraki et al, 2000 ; Bolton-Smith et al, 2007; Tsugawa et al, 2008; Binkley et al 2009; Rønn et al, 2016).  In Australia, women with the lowest intake of vitamin K1 had the highest long-term risk for fractures.  Women were followed over 14.5 years and their intake of vitamin K was measured via osteocalcin blood levels (Sim et al, 2022).

Japanese Shorinji Kempo athletes were given a medical exam showing that 44% of them had experienced a sports-related fracture during practice, 75% had a lower daily vitamin D intake, and 94% had a lower daily vitamin K intake.  The authors indicated that the athletes needed to improve their bone mass, bone metabolism and improve their nutrition, including vitamin K in order to improve their physical function (Sumida et al, 2012).  Improving the intake of vitamin K with an increased intake of green leafy vegetables substantially improved osteocalcin markers of bone health suggesting increased entry of osteocalcin into the bone matrix, improvement of bone quality and lower fracture risk (Sim, et al, 2020).  

Large-scale epidemiological studies on the relationship between vitamin K and fracture risk have been conducted. One of the largest studies in this matter is a prospective analysis conducted within the Nurse' Health Study performed with 72,327 women between 38 and 74 years of age, with a 10-year follow-up. In that study, subjects with a vitamin K1 intake more than 109 μg/day presented a 30% lower risk of hip fracture than women with a lower intake (Feskanich et al, 1999).  An epidemiological study conducted in North America revealed low vitamin K intake to be associated with an increased risk of hip fracture (Booth et al, 2000). 

A four-year study was conducted with postmenopausal Canadian women with osteopenia and normal levels of vitamin D who were taking vitamin K1 (phylloquinone) 500 mcg/day.  The women taking vitamin K had fewer clinical fractures than the placebo group of women (Cheung et al, 2008). Another study showed that a low concentration of vitamin K1 in elderly Asian patients was associated with an increased risk of fractures in both sexes (Nakano et al, 2011). Recently, postmenopausal women with osteoporosis were studied, and the results showed that those with fractures had a significantly lower value of vitamin K1 (Yaegashi et al, 2008; Torbergsen et al, 2015; Moore et al, 2020).

Another systematic review analyzed both BMD and fracture risk with K1 or MK-4 supplements. The authors found that all thirteen trials except one showed less bone loss (measured by BMD) in patients supplemented with either type of vitamin K. They also found that MK-4 supplements caused a reduction in all fracture types;  hip fractures showed a 77% reduction, vertebral fractures a 60% reduction and all nonvertebral fractures 81% reduction (Cockayne et al, 2006).

Low plasma concentrations of vitamin K are associated with a high risk of bone fractures in both northern Europeans and Asian populations of both sexes (Yaegashi et al, 2008; Torbergsen et al, 2015).The NOREPOS study (Norwegian Epidemiologic Osteoporosis Study) showed that low serum levels of vitamin K1 were associated with a 50% higher risk for hip fractures (Finnes et al, 2016).  The Perth Longitudinal study of aging Women in Australia showed that women who ate 125 g of dark leafy vegetables or more than 100 micrograms of vitamin K1, were 31% less likely to have any fractures (Sim et al, 2020). Lead author Dr. Marc Sim said the results further solidified vitamin K1 as a factor in fracture risk.

A pilot study indicated that children with low vitamin K2 status may be at greater risk of developing low-energy bone fractures. A low-energy bone fracture is defined as a fracture resulting from a fall that happens from standing height or lower (Popko et al, 2018; Karpinski et al, 2017).

A recent meta-analysis involving a total of 80,982 participants, showed an inverse association between dietary vitamin K1 intake and the risk of fractures.  Those subjects with the highest intake of vitamin K presented a 22% reduction in fracture risk (Hao et al, 2017). The prevalence of VK deficiency was found to be higher in older patients (mean age 80.0) with hip fractures than those without (Bultynck et al, 2020).

Natto is a Japanese delicacy and is made of fermented soybeans, which have the highest concentration of MK7.  Regional studies have shown that natto consumption reduces incidences of hip fractures in women in Japan.  A cross-sectional study comparing the serum vitamin K2 levels in Asian and European women found that the presence of natto in the diet of the Japanese population was associated with increased serum levels of MK-7, and were associated with a reduced osteoporotic fracture risk compared to the women from the UK (Kaneki et al, 2001; Yaegashi et al, 2008).  Recently, a large prospective cohort study revealed that natto intake is inversely correlated with fracture risk (Kojima et al, 2019).

Stress fractures occur due to repetitive loading of the bones with stress, rather than a single traumatic event. They can occur in all bones of the lower extremity, particularly in people predisposed to repetitive strain, such as athletes. A recent report was published of a 13 year-old basketball player with right foot pain.  After six weeks of standard treatment, his pain had increased.  When testing showed he was low in vitamin K levels, he was told to add green vegetables to his diet.  He returned to the sport in six months and his physician felt that correcting the vitamin K deficiency was an important factor (Bayramoğlu et al, 2017).

Osteoporosis
Osteoporosis is characterized as osteo (bone) porosis (holes in the bone), and it develops when bone mineral density and bone mass decreases.  A diagnosis of osteoporosis indicates that new bone creation hasn't keep up with old bone removal.  It has been demonstrated that K intake decreases bone resorption markers and increases bone formation, improving the balance between bone formation and resorption (Crăciun et al, 1998).

Osteoclast cells resorb bone in the process of remodeling.  If there is too much resorption, bone can become weakened and diseased.  Numerous studies have found that vitamin K2 suppresses osteoclast cells, and increased the rate of their death and that matrix Gla protein mediated these effects (Akedo et al, 1992; Kameda et al, 1996).  MK7 significantly increased the synthesis of osteoblast cells, which build bone (Yamaguchi  et al, 2001; Koshihara et al, 2003; Yamaguchi & Weitzmann, 2011; Hara et al, 1995), the synthesis of interleukin (IL)‐1α and IL-6  (Akbari & Rasouli‐Ghahroudi, 2018; Wang et al, 2022), and vitamin D3 (Miyake et al, 2002; Poon et al, 2015).

Research indicates that regular intake of vitamin K is associated with reducing the risk of osteoporosis (Rachner et al, 2011).  In Japan, vitamin K2 supplements are an approved treatment for osteoporosis (Iwamoto et al, 2009).  Early studies found that postmenopausal women with reduced bone mineral density presented with lower levels of vitamin K1 and K2 (Hodges et al, 1993; Kanai et al, 1997) and that vitamin K levels were a useful tool to assess diseases such as osteoporosis (Heiss et al, 2004).  Recently, postmenopausal women with osteoporosis were studied, and the results showed that those with fractures had a significantly lower value of vitamin K1 (Moore et al, 2020).

In an interventional study, osteoporotic patients were given 45 mg of MK4 per day, for two years, compared to a control group who did not receive MK4.  The intervention group showed a reduced incidence of bone fractures (Shiraki, 2000). This same research group studied female osteoporotic patients receiving MK4, and found that those with more carboxylated or active osteocalcin circulating, had a lower incidence of new fractures (Shiraki et al, 2010). Research has found that serum K1 was significantly lower and was positively correlated with lumbar spine BMD in postmenopausal women with osteoporosis (Jaghsi et al 2018). 

A meta-analysis (Huang et al, 2015) looked at the role of vitamin K2 supplements both in BMD and fracture. Including 19 studies with 6759 participants, the authors found that K2 supplements improved significantly middle- and long-term vertebral BMD and long-term forearm BMD in postmenopausal women with osteoporosis, and reduced fracture risk in women with osteoporosis. In this review, postmenopausal women who took MK7 for three years, showed less bone loss than those who did not take Mk7 (Knapen et al, 2013).

--Osteoarthritis
Osteoarthritis is a common condition that makes a person’s joints stiff and painful. It is characterized by pathological changes in joint tissues, causing joint pain and impaired function (Hawellek et al, 2016).  Both cartilage and meniscal calcification have been implicated in arthritis (Fuerst et al, 2009; Sun et al, 2010).  It becomes very difficult to move and exercise with arthritis. 

The cartilage in joints contain proteins that are vitamin K dependent, such as matrix Gla protein.  Research on arthritic cartilage indicate that the matrix Gla protein in the diseased tissue is primarily uncarboxylated and is less functional, whereas in healthy cartilage, the MGP is carboxylated and functional (Wallin et al, 2010).  The Health ABC (Healthy, Aging, and Body Composition) study looked at community dwelling elderly, average age 74, followed for three years, and found a higher level of uncarboxylated MGP was associated with meniscus damage, osteophytes, bone marrow lesions, and other damage.  In terms of mobility, the Health ABC study found that circulating low vitamin K level was associated with mobility limitation and disability.  Similarly, El-Brashy (et al. 2016) showed that vitamin K was associated with significantly decreased cartilage thickness at medial, lateral, and sulcus condyles, as revealed by ultrasound assessment, as well as arthritis progression.

Research shows that vitamin K improves markers of arthritis. In epidemiological studies, low circulating vitamin K was associated with greater prevalence of hand and knee arthritis (Neogi et al, 2006) and with greater arthritis progression in the knee, along with cartilage loss longitudinally (Misra et al, 2013). Low blood levels of vitamin K predicted articular cartilage and meniscus damage.  Sub-analysis based on race showed that low uncarboxylated MGP was associated with articular damage in African Americans, while non-detectable plasma vitamin K was associated with meniscal damage, among Caucasians (Shea et al, 2015).

In summary, evidence supports the role of Vitamin K2 in maintenance of bone health in numerous ways; increasing bone strength and density, reducing the risk of osteoporosis, increasing bone mineral content, inhibiting bone resorption, decreasing fracture risk, reducing the impact of arthritis, and upregulating cOC and carboxylated‐MGP levels.   Exercise requires strong bones, and vitamin K supports that need in multiple ways. 

While this page is reviewing the role of vitamin K and exercise, it is also important to note that there is significant research on the relationship of magnesium and vitamin D, along with vitamin K in making necessary contributions to bone health.  Everyone who wishes to be physically active should absolutely take all three nutrients. 

Nutrients work as integral parts of complex metabolic networks.  Vitamin D is a necessary cofactor with vitamin K in the formation of healthy bone and thus plays a role in osteoporosis, fragility fractures, stress fractures, and fracture healing. Athletes undertake mechanical loading from training or competition which is associated with an increase in bone stress, calling on vitamin D to help their bones respond (Rantalainen et al, 2011).  A study has shown that low intake of vitamin D in NFL players was significantly associated with bone fractures (Shindle et al, 2011).  Studies of Finnish military recruits showed that a low D concentration had a significantly increased risk of a stress fracture (Ruohola et al, 2006; Välimäki et al 2004). 

Magnesium is not synthesized by humans, consequently it must be ingested through food or supplements.  It is involved in practically every major metabolic and biochemical process within the cell and is responsible for numerous functions in the body, including bone development, neuromuscular function, signaling pathways, energy storage and transfer, glucose, lipid and protein metabolism, DNA and RNA stability, and cell proliferation (Fiorentini et al, 2021).  Magnesium is crucial for maintaining strong bones as it supports the activation of vitamin D and the absorption of calcium (Saminathan, 2003; Uwitonze & Razzaque, 2028).  It also induces osteoblast differentiation, which are the cells that build bone (Lu et al, 2017).  Deficiencies are associated with brittle bones (Boskey et al, 1992).  If you wish to test your levels, RBC (Red Blood Cell) Magnesium would be the test to order.

 

MUSCLES
Bone and muscle are linked anatomically, biochemically, and metabolically, and there is crosstalk between the two systems (Battafarano et al, 2020; Kirk et al, 2020; Smith et al, 2021).  While Vitamin K supports bone health, it also has been linked to greater muscle mass, muscle strength, and greater exercise capacity.

Skeletal muscle is involved in postural support, breathing and body temperature regulation, and the generation of force and power during voluntary movements, (Delezie & Handschin, 2018).  Skeletal muscle is the only type of muscle a person can voluntarily control, and it is the most abundant organ of the human body.  The body has about 6000 skeletal muscles, accounting for 40-50% of the total body weight (Schnyder et al, 2015; Janssen et al, 2000; Strasser & Burtscher, 2018).  Men have about 36% more skeletal muscle mass than women. People who are tall or overweight also tend to have higher muscle mass. Muscle mass decreases with age in both men and women.

Skeletal muscle is composed of bundles of muscle fibers called myofibers that span the length of the muscle.  Each myofiber represents a muscle cell with its basic functional unit, the sarcomere, that enables the muscle to contract.  Movement of sarcomeres leads to the generation of biochemical signals (myokines) that are released by the muscle, and which act on the myofibers and on other tissues.

Muscle fibers can be classified as type I, type IIa and type IIb fibers. Type I are referred to as slow twitch and type IIb are known as fast twitch.  High mitochondrial content increases the oxidative ability and endurance in the muscles and Type I fibers have the highest mitochondrial content (Jacobs et al, 1985; Mahatme et al, 2022; Psilander, 2014; van der Zwaard et al, 2016). Exercise leads to the development of more mitochondria in muscle (Harper et al, 2021).

Muscle responds to its environment.  If there is inactivity, muscle withers and atrophies.  If the environment includes movement and exercise, muscle adapts.  As a form of physical activity, exercise is generally dichotomized into resistance training (RT) and aerobic training (AT) categories. The muscle adaptations associated with resistance training are due to the synthesis of new myofibrillar and mitochondrial proteins that increase muscle size and strength, respectively (Carapeto et al, 2021; Flück & Hoppeler, 2003; Egan & Sharpes, 2023; Furrer et al, 2023.  Adaptations to aerobic exercise and training include an increase in the capillary supply, size, and number of muscle mitochondria to greatly enhance aerobic metabolism (Yan et al, 2012; Oliveira et al, 2021). 

 --Endocrine Organ
Skeletal muscle is no longer seen as merely a machine for movement, but an endocrine organ, an immune reservoir, and an indicator of physiological wellness. Skeletal muscles play a crucial role in whole-body metabolism, as muscle is a major storage site for glucose, lipids, and amino acids.  During resting periods, skeletal muscles store energy, in the form of triglycerides and glycogen, which are then released as needed/to meet the demand during exercise (Karsenty & Mera, 2018; Mera et al, 2018; Lavin et al, 2022).

The endocrine system is a group of glands and cells in the body that make hormones and release them into the blood. Skeletal muscle releases myokines in response to contraction, which can influence metabolism in other tissues and organs. (Pedersen & Fabbraio, 2008; Clifford & Tschakovsky, 2008). 

--Fat
Fat, in the form of triglycerides, is stored as lipid droplets inside muscle fibers (van Loon et al, 2001).  Triglycerides are composed of three fatty acids attached to a molecule of glycerol.    Intramuscular triglycerides (IMCL) are easily available and in close proximity to the muscle mitochondria.  During exercise, the triglycerides are broken down into glycerol and free fatty acids in a process called lipolysis (Ogasawara et al, 2015; Watt & Spriet, 2010; Zechner et al, 2009). The fatty acids are released to the circulation and directed into muscle cells for energy.  Once inside the muscle cell, fatty acids are transported to the mitochondria (i.e., energy factory of the cell) to be broken down to produce ATP as fuel for working muscles (Thompson et al, 2012).

Intramuscular triglyceride generally supplies the fatty acids for up to 2 hours of continuous exercise. Individuals with higher fitness have a greater storage capacity and ability to metabolize intramuscular triglyceride.  Endurance-trained athletes rely more heavily on IMCL to fuel exercise.

--Oxygen
During exercise, an important function of the cardiovascular system is to supply oxygen to the active muscles according to the demand.  Just how much oxygen your muscles will use depends on two processes: the blood flow to the muscles and the extraction of oxygen from the blood into the muscle tissue, known as perfusion. In this process, the muscle produces several metabolic byproducts, such as adenosine, hydrogen ions and carbon dioxide.  As these byproducts leave the muscle cells, they cause the capillaries within the muscle to expand or dilate, leading to increased blood flow that in turn, delivers more oxygenated blood to the working muscle (Andersen & Saltin, 1985; Rowell et al, 1986; Wagner, 1996; Koskolou et al, 1997; Delp & Laughlin, 1998; González -Alonso et al, 2022).

Working muscles can take oxygen out of the blood three times better than your resting muscles.  Some believe that maximal oxygen uptake is dependent on the muscle fiber oxidative capacity (van der Zwaand et al, 1985; Wisloff et al, 1998). 

Anything that can affect oxygen intake or blood flow can impact the amount of oxygen delivered to working muscles during exercise, such as restrictions in blood flow. Cardiac function and vascular health can help or limit the ability of the circulatory system the meet the increasing demands of muscle and tissues during whole-body exercise. Lung health or disease can impair the ability of the lungs to exchange oxygen, meaning there is less oxygen to carry in the blood stream to muscles. 

-VITAMIN K AND MUSCLE
The research shows that vitamin K helps with better physical performance, larger muscle mass, muscle strength, and reduces muscle cramping.

--Better Physical Performance
The first study on the role of vitamin K and physical performance was carried out in 2016, where 1,089 elderly participants of the Health, Ageing and Body Composition Study (Health ABC) had their lower extremity muscle function assessed.  It was found that vitamin K1 was significantly associated with better physical function, and this effect was maintained over 5 years of follow-up (Shea et al, 2016).

The SarcoPhAge project is an ongoing longitudinal study in Belgium of the elderly who are living independently.  Those who were diagnosed with sarcopenia consumed significantly lower amounts of two macronutrients (proteins, lipids) and five micronutrients (potassium, magnesium, phosphorus, iron, and vitamin K) than non-sarcopenic subjects. (Beaudart et al, 2016).

The Longitudinal Aging Study Amsterdam (LASA) followed women for 14 years, measuring their biochemical markers of vitamin K along with measures of strength.  They found that higher ucMGP concentrations (indicating low vitamin K intake) were associated with lower handgrip strength and calf circumference and a lower physical performance (van Ballegooijen et al, 2018; Machado-Fraguo et al, 2010). 

Mouse models established that osteocalcin can be considered a bone hormone that can regulate tissue, including muscle (Lee et al, 2007).  Mice genetically modified to not have osteocalcin, demonstrated reduced muscle mass and decreased muscle fiber (Ducy et al, 1996).  Building on this, they determined that the receptor of osteocalcin in muscle cells was GPRC6A and then using genetically modified mice that lacked that receptor, found that injections of osteocalcin could not increase the exercise capacity of these animals; indicating that osteocalcin signaling is specifically required in myofibers for exercise adaptation.  Research has been able to show that muscle uptake of glucose and fatty acids was increased upon exposure to osteocalcin in vitro, meaning that osteocalcin signaling supports glucose and fatty acid utilization during exercise  (Lin et al, 2017; Tsuka et al, 2015; Pi et al, 2016; Moser & van der Eerden, 2019; Mera et al, 2016; Alonso et al, 2022).  Keep in mind that adequate amounts of vitamin K intake are necessary for osteocalcin to be part of this cycle.

--Muscle Mass
Observational studies conducted on patients with sarcopenia showed that high levels of vitamin K were associated with muscle strength, large muscle mass and high physical performance.  The beneficial effect of vitamin K on muscle quality was best represented by physical performance scores rather than muscle mass (Azuma & Inoue, 2019).

Vitamin K deficiency is correlated with progressive reductions in muscle mass.  The authors concluded that vitamin K2 moderates skeletal muscle mitochondria, and recommended studies on vitamin K2 supplementation to prevent muscle mass loss (Rønning et al, 2018; Simes et al, 2019). A lab study showed that vitamin K2 increased slow twitch muscle fibers and improved mitochondrial function (Su et al, 2022). 

--Muscle Strength
Handgrip indicates muscle strength and is directly related to lower-extremity strength. Calf circumference indicates skeletal muscle mass and is associated with higher strength (Jakobsen et al, 2010; Rolland et al, 2003). A longitudinal cohort study conducted in community-dwelling adults analyzed the association between vitamin K status and physical functioning over 13 years. Low vitamin K status was associated with lower handgrip strength, smaller calf circumference, and poorer functional performance (Ballegooijena et al, 2018).

--Leg Cramps
Leg cramps are a distressing problem characterized by involuntary, painful, sudden contractions of the skeletal muscles, accompanied by pain or muscle hardening, and are typically found in the lower extremities.  It affects about 30% of people over the age of sixty, and 50% of people over the age of 80 (Naylor et al, 1994; Abdulla et al, 1999).  A study using MK7, at a dose of 100 mcg/day for three months relieved muscle cramps (Mehta et al, 2010).

To further elucidate the effects of MK-7 on cramps, a clinical trial showed that vitamin K2 reduced the frequency and severity of muscle cramps in patients on dialysis.  Those who received 360 ug/day of K2 showed a significant decrease in the frequency of muscle cramps within eight weeks, with a further reduction in the next eight weeks.  The group receiving the placebo had no significant reduction in the frequency of cramps.  The vitamin K benefit was manifested by decreased frequency, shortened duration, and weakened intensity of cramping Furthermore, the improvements went away when vitamin K2 was replaced with the placebo (Xu et al, 2022).

Role of Osteocalcin
Osteocalcin impacts exercise through its role in glucose metabolism and its role in inducing the expression of interleukin6, a myokine that increases exercise capacity (Komori, 2020).

When osteocalcin is released during the process of resorption in bone remodeling, it is uncarboxylated, known as ucOC.  This form enters circulation and stimulates beta cells in the pancreas to proliferate to secrete insulin after food intake (Lee et al, 2007; Ferron et al, 2010, Fulzele, et al, 2010; Yoshikawa et al, 2011).  This is important because insulin is the primary hormone that increases the deposits of glucose and fatty acid storage into muscle, as glycogen, and triglycerides, respectively.  Insulin gets the glycogen and lipids stored into skeletal muscle, so they will be available for energy/exercise when needed.

Conversely, there is a positive loop between bone and the pancreas, which impacts glucose homeostasis.  When osteocalcin is released into circulation, it affects the release of insulin.  The insulin then signals to osteoblast cells which promotes osteoclast cells in bone to release more osteocalcin during bone resorption, which in turn triggers insulin making osteocalcin a key element in the insulin cycle (Ng & Martin, 2009; Ferron et al, 2010; Faienza et al, 2015; Lombardi et al, 2015; Lombardi, 2019).

--Osteocalcin and muscle strength
A low undercarboxylated OCN/OCN ratio was associated with lower muscle strength in young women (Levinger et al, 2014).  In order to investigate the role of undercarboxylated OCN in muscle and whether it could be a biomarker for bone-muscle interaction in adults, a randomized controlled multicenter crossover clinical trial called the Wellderly Project has been set up.  This study aims to recruit men and women over 60-years-old, measure the undercarboxylated OCN levels in serum before and after acute exercise, and correlate these values with parameters of muscle quality (Smith et al, 2021).

It has been demonstrated that carboxylated osteocalcin correlates with muscle mass and risk of fall in postmenopausal women.  This suggests that older women, with low intake of vitamin K, have less muscle mass and a moderate-severe risk of fall (Vitale et al, 2021).

Uncarboxylated or inactive osteocalcin has been implicated in muscle hypertrophy and strength.  Mice with OCN deletions have lower muscle mass (Lin et al, 2016)], and the administration of ucOCN increased muscle mass in older mice (Mera et al, 2016).

--Osteocalcin, exercise capacity and age.
Osteocalcin naturally declines in humans as we age, beginning in women at age 30 and in men at age 50. This decrease in circulating bioactive OCN occurs at the same time as the ability to perform exercise declines (Mera et al, 2016a).  However, during exercise in both mice and humans, the levels of osteocalcin in the blood do increase, depending on age (Levinger et al, 2014; Rahimi et al, 2020; Rahimi et al, 2021).

A study of Japanese community dwelling older adults found that low levels of osteocalcin, reflecting K intake, was associated with frailty, slow walking speed, and low activity (Azuma et al, 2022).

To investigate whether osteocalcin levels were affecting exercise performance, Karsenty and his colleagues tested mice genetically engineered so osteocalcin could not signal properly in their muscles. Without osteocalcin muscle signaling, the mice ran 20%-30% less time and distance than their healthy counterparts before reaching exhaustion.  It was concluded that the osteocalcin signaling in myofibers favors adaptation to exercise because it promotes the uptake of glucose and fatty acids, a necessary step to create energy (Mera et al, 2016a; Karsenty & Olsen, 2016).

Building on that research, the same team tested whether injections of osteocalcin could increase the exercise capacity of older unmodified mice. At baseline, the researchers observed that in 3-month-old adult mice, osteocalcin levels spiked approximately four times more than the levels in 12-month-old mice. when the rodents ran for 40 minutes on a treadmill. The 3-month-old mice could run for about 1,200 meters before becoming exhausted, while the 12-month-old mice could only run half of that distance, 600 meters. 

The mice were then given a single injection of exogenous uncarboxylated OCN immediately before exercise.  The results showed that the osteocalcin not only increased the exercise capacity of young mice by 20%, but also restored aerobic endurance in older mice to the level seen in young adult mice.  The osteocalcin injections were able to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This injection increased circulating osteocalcin levels more than 4-fold and conferred to these older mice the ability to run the same time and distance as 3-month-old untreated mice (Mera et al, 2016a).  Additionally, in another step, they arranged for the chronic delivery of osteocalcin through mini-pumps (90 ng/hour) for 28 days and found that the circulating osteocalcin levels as well as the time and distance 10-month-old unmodified mice could run on a treadmill before exhaustion also improved.

It was concluded that osteocalcin has this effect by stimulating glucose and fatty acid uptake and usage by muscles, ensuring that the nutrients are stocked in the muscle tissue, and ensuring that those nutrients can be accessed during exercise. (Mera et al, 2016a; Lacombe et al, 2020)

These experiments highlighted the therapeutic potential of OCN to reverse the age-induced decline in exercise capacity and muscle mass observed in mice, and humans. This study not only showed that osteocalcin is necessary and sufficient to increase exercise capacity; but that osteocalcin has anti-geronic properties, that is, it has the ability, when administered to older animals, to ameliorate the consequences of aging (Mera et al, 2016; Diaz-Franco et al, 2019). Gerard Karsenty, a geneticist at the Columbia University Medical Center and senior author on the study. 

"The hormone is powerful enough to reconstitute, in older animals, the muscle function of young animals….It's never been shown before that bone actually influences muscle in any way.  Osteocalcin is not the only hormone responsible for adaptation to exercise in mice and humans, but it is the only known bone-derived hormone that increases exercise capacity. This may be one way to treat age-related decline in muscle function in humans." 

OCN supports muscle function during exercise through an additional mechanism: it favors the expression and release of interleukin 6 (IL-6), the first molecule found to be secreted into blood in response to muscle contraction (Steensberg et al, 2000; Pedersen & Febbraio, 2008).  Interleukin 6 is believed to increase exercise capacity by enhancing glucose production in the liver, lipolysis in white fat tissue, and glucose uptake by myofibers (Pedersen & Febbraio, 2012; Pal et al, 2014; Lin et al, 2017).  Research with mice revealed that muscle-derived IL-6 is necessary for optimum ability to exercise Chowdhury et al, 2020). 

MITOCHONDRIA

The human body needs energy to function, and food is the fuel source for energy. Foods are made up of nutritional components called fats, carbohydrates, and proteins. Through digestion, foods are deconstructed into their most basic states, called glucose, fatty acids, and amino acids. Once these nutrients are broken down, they are transported through the blood to either be used in a metabolic pathway or stored for later use.  Carbohydrates are generally used for short-term energy needs, while fats are used for long-term energy needs. Proteins can supply energy, but are often used for building muscle, not providing energy (Da Poian, et al, 2010; Hargreaves & Spriet, 2018).

Food is converted into an important form of chemical energy, adenosine triphosphate or ATP. Mitochondria mediate this conversion of metabolic substrates to adenosine triphosphate (ATP), the immediate usable form of chemical energy utilized for most cellular functions. Mitochondria are popularly known as the ‘powerhouses of the cell’, as they provide about 80% of the energy for cell life activities.  Only a small amount of ATP is stored within the body, which is not a significant energy reserve.  

Mitochondria are present in most cells in the human body.  They are double-membrane organelles, with an outer membrane embedded with transport proteins, which is surrounded by the inner mitochondrial membrane (Hood et al, 2019).  The inner mitochondrial membrane is folded into tubular structures known as cristae. The cristae are the site of the respiratory chain complexes, consisting of the electron transport chain (ETC) (Pileggi et al, 2021) which is a series of four protein complexes that create an electrochemical gradient that leads to the creation of ATP, and the release of energy (Ahmad et al, 2022).

Within the mammalian skeletal muscle, mitochondria form large networks, which allows rapid electrical interconnection and communication between adjacent organelles to support the bioenergetic needs of skeletal muscle (Boushel et al 2014; Glancy et al, 2017).  This mitochondrial network is maintained by dynamic processes of biogenesis and fusion and is balanced by opposing processes of fission and mitophagy (Palikaras et al, 2014; Ju et al, 2016).

Mitochondrial Dynamics

Studies have revealed that mitochondria do not sit still, but are dynamically regulated, undergoing repeated rounds of fusion and fission and even moving around the cell (Liesa et al, 2009).  Their plasticity allows them to adjust to demands such as exercise.  (Holloszy et al, 1970; Dohm et al, 1973; Cartoni et al, 2005; Ding et al, 2010; Perry et al, 2010; Smuder et al, 2011; Memme et al, 2021). 

Mitochondrial fission is a process in which daughter mitochondria are produced from the main mitochondria.  It is initiated to remove damaged and dysfunctional mitochondria from the mitochondrial pool.  Mitochondrial fission are critical for the maintenance of a healthy network  (Mishra and Chan, 2016). 

Mitochondrial fusion is the merging of two or more mitochondria in close contact to form one mitochondrion.  In fusion, newly formed mitochondria are adjoined to neighboring organelles to increase their capacity for ATP synthesis and other processes.  Fusion helps expand and elongate the mitochondrial reticulum, with healthy, exercise-trained individuals having more complex and extensive forms (Karbowski et al, 2004; Spinelli & Haigis, 2018). 

Mitochondria continuously undergo events of fission and fusion to respond to the energetic challenges of the cell (Pernas & Scoranno, 2016) which contributes to a healthy mitochondrial population during development and while we age (Casuso et al, 2020; Huertas et al, 2021; Sprenger & Langer, 2019).  

Mitophagy is the selective degradation of dysfunctional mitochondria into their basic lipids and amino acids to support future synthesis (Miller & Hamilton, 2012; Hood et al, 2019). Mitophagy is an important process towards maintaining the health of the network.  

Several mechanisms have been described that initiate the process of mitophagy; however, the PINK1/Parkin pathway is believed to be the main pathway.  PINK1 is a mitochondria-targeted protein located in the outer membrane of the mitochondria, that is constantly imported and processed through the mitochondria.  When mitochondria are damaged, the cell recognizes and clears the dysfunctional mitochondria through the Pink1 protein (Vos et al, 2012; Tang et al, 2022). The Pink1 protein is related to longevity (Mouton-Liger et al, 2017; Si et al, 2019).

Absence of either PINK1 or Parkin results in an accumulation of dysfunctional and fragmented mitochondria and can result in the accumulation of ROS in damaged mitochondria, leading to cellular oxidative stress and disease. Therefore, proper regulation of the PINK1/Parkin signaling pathway is an effective measure to block the expansion of mitochondrial damage (Greene et al, 2012).

Research on Exercise and Mitochondria
In 1967, John Holloszy published the first direct evidence that exercise training promotes mitochondrial biogenesis in skeletal muscle several ways. This seminal study showed that a strenuous program of treadmill running in rats led to significant increases in mitochondrial protein and enzyme activity in recruited skeletal muscles. Later research showed that exercise training increases the synthesis of mitochondrial proteins in human skeletal muscle (Wilkinson et al, 2008; Miller & Hamilton, 2012; Scalzo et al, 2014; Ju, 2017; Oliveira & Hood, 2019).

Exercise training induces mitochondrial fusion and fission to sustain energy requirements (Bori et al, 2012; Iqbal et al, 2013; Konopka and Sreekumaran Nair 2013).  Studies show that exercise improves mitochondrial quality and function by stimulating their turnover (Safdar et al, 2011; Cartee et al, 2016; Joseph et al, 2016).  Also, exercise training has been found to trigger mitophagy, leading to the degradation and removal of abnormal mitochondria (Vainshtein et al, 2015a; Laker et al, 2017; Yoshioka et al, 2019; Memme et al, 2019).  Moreover, SC assembly in human skeletal muscles following exercise was associated with increased mitochondrial respiration (Greggio et al, 2017).

Mitochondrial biogenesis is an increase in muscle mitochondrial volume and composition, which leads to an improved capacity for substrate oxidation, greater mitochondrial content, and increased mitochondrial respiration.  Exercise training, including endurance and resistance exercise, stimulates mitochondrial biogenesis (Holloszy, 1967; Spina et al, 1996; Baar et al, 2002; Geng et al, 2010; Bishop et al, 2014; Jung et al, 2014; Delezie & Handschin, 2018; Gibala et al, 2012; Granata et al, 2017; Sorriento et al, 2021).

Skeletal muscle mitochondrial content is known to be strongly influenced by physical activity, with an increase in content with exercise training in healthy individuals.  These activity‐dependent physiological effects rely on the type of exercise (aerobic endurance vs. resistance strength), as well as on its frequency, intensity, and duration (Hoppeler & Fluck, 2003: Egan & Zierath, 2013; Zampieri et al, 2016; Touron et al, 2021). 

Several studies have shown that mitochondrial function is not affected by chronological aging, but rather by decreases in physical activity that normally occurs with aging (Barrientos et al, 1996; Brierley et al, 1996; Lazarus et al, 2016).  No differences in mitochondrial content and respiration were observed between young and old subjects matched for physical activity, both engaged in moderate-to vigorous-intensity exercise training (Gouspillou et al, 2014).  

-Mitochondria and Vitamin K

Research has shown that vitamin K has an important role of supporting mitophagy, the mechanism of finding and degrading damaged mitochondria (Drake et al, 2015; Ploumi et al, 2017; Anzell et al, 2018]. In normal mitochondria, the PINK1 protein can function as a sensor for damaged mitochondria, mediating the mitophagy that clears out the damage (Gomes et al, 2013; Tang et al, 2022).  When there is mitochondrial damage, PINK1 is not imported into the mitochondria (Jin et al, 2012), resulting in an accumulation of dysfunctional and fragmented mitochondria which can result in the accumulation of ROS in damaged mitochondria, leading to cellular oxidative stress (Geisler et al, 2010; Greene et al, 2012). 

Importantly, research has shown that vitamin K2 (MK4) rescued severe mitochondrial defects caused by mutations in the PINK1 gene. Vitamin K2 served as a mitochondrial electron carrier and rescued mitochondrial dysfunction due to Pink1 protein deficiency (Vos et al, 2012). 

Another recent study found that vitamin K2 treatments promoted mitophagy and alleviated damage to cells.  In labs, SH-SY5Y cells serve as a model for neurodegenerative disorders. In the study, SH-SY5Y cells were stimulated with 6-hydroxydopamine (6-OHDA) (often used in research to induce Parkinson’s disease). In the presence of 6-OHDA, cell viability was reduced, the mitochondrial membrane potential was decreased, reactive oxygen species (ROS) accumulated, and there was abnormal mitochondrial fission and fusion.  However, when MK4 was added to the cells, it significantly suppressed damage from 6-OHDA, enabling the cells to maintain the important balance of mitochondrial fusion and fission (Tang et al, 2022).  These results suggest that vitamin K2 improves mitochondrial dysfunction and alleviates cell damage by regulating the mitochondrial quality-control system (Su et al, 2021).

Rotenone, a widely used pesticide, can selectively inhibit aspects of the mitochondrial electron transport chain, inducing oxidative stress  and neurodegeneration (Martinez & Greenamyre, 2012; Radad et al, 2006) Research found that MK4 inhibits  rotenone-induced damage, and significantly decreased reactive oxygen species (ROS) production. In addition, MK-4 represses microglial neuronal cell death (Yu et al, 2016].

The majority of cells in the central nervous system are astrocytes.  In a recent study, when astrocytes were pretreated with MK7, then deprived of oxygen, there was reduced inflammation, reactive oxygen species production was inhibited, and ATP production was increased (Yang et al, 2020). However, in a 2019 study using human CoQ10‐deficient cell lines and yeast carrying mutations in genes required for CoQ6 biosynthesis, Vitamin K2, despite reaching mitochondria, restored neither electron flow in the respiratory chain nor ATP synthesis (Cerqua et al, 2019). It was considered that the role of VitK2 as electron carrier (if confirmed) might probably be restricted to Drosophila, rather than being a general phenomenon in eukaryotic cells.

Summary
On this page, we have reviewed the basic components of your body’s response to the biophysiology of movement/exercise, which include the cardiovascular system, the lungs, bones, muscle, and mitochondria.  These systems respond to movement, and each of them can adapt and improve to the demands of movement and exercise. 

There is a wealth of research detailing the role of vitamin K in each of these systems, particularly for the cardiovascular system, and bones.  Research has just begun looking at the relationship of vitamin K to exercise outcomes, and the initial findings are exciting, showing that in just 8 weeks, a person can significantly improve their VO2 max by taking MK7.

K serves as the catalyst for the organ systems and is key to fitness and physical activity.  With adequate availability of vitamin K, these organ systems are best prepped for peak training and performance (Crintea et al, 2019; Brancaccio et al, 2022).

Your body is made to move.  If you move regularly, even to the point of exercising or training, your body will respond and with vitamin K, that response will be enhanced. 

 

REFERENCES

1960s

Harris P, Heath D, Apostolopoulos A. Extensibility of the human pulmonary trunk. Br Heart J. 1965;27:651–659. 
The mechanical properties of the walls of blood vessels have an important influence on the flow of blood and passage of pulse waves along them. An early study using cadavers, concluded that arterial extensibility decreased with increasing age, related to a decrease in elastic tissue and an increase in collagen that accompanies aging.

Holloszy J.O. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J. Biol. Chem. 1967;242:2278–2282.
Holloszy showed for the first time that exercise training in rodents resulted in a doubling of skeletal muscle mitochondria, ushering in skeletal muscle plasticity research. showing that endurance exercise training resulted in substantial mitochondrial adaptations in rodent skeletal muscle. He demonstrated that high-intensity running (in contrast to swimming) for progressively longer durations up to 2 h/day, 5 days/wk for 12 week, nearly doubled the oxidative capacity, respiratory enzyme activity, and mitochondrial biogenesis in rodent limb muscles.  Mitochondria from muscles of exercised animals exhibited a high level of respiratory control and a tightly coupled oxidative phosphorylation profile.  Thus, the increase in electron transport capacity was associated with a concomitant rise in the capacity to produce adenosine triphosphate. This adaptation may partially account for the increase in aerobic work capacity that occurs with regularly performed, prolonged exercise. 

1970s

Dohm GL, Huston RL, Askew EW, Fleshood HL. 1973. Effects of exercise, training, and diet on muscle citric acid cycle enzyme activityCan J Biochem. 1973;51:849–854.

Gonza ER, Marble AE, Shaw A, Holland JG. Age-related changes in the mechanics of the aorta and pulmonary artery of man. J Appl Physiol1974;36:407–411. 

Lanyon LE, Hampson WGJ, Goodship AE, Shah JS.  Bone deformation recorded in vivo from strain gauges attached to the human tibial shaft.  Act Orthopaedica Scandinavica.  1975;46(2):256-268.
A strain gauge rosette was attached to the midshaft of a man's tibia. This demonstrated that during every stride the bone surface was subjected to a number of discrete deformation cycles. During each cycle the bone was deformed from a particular direction, released at least partially and then deformed from another direction. This feature has been observed from a number of sites in experimental animals. The largest deformation occurred while the subject was running; the principal tension then reached 850 microstrain applied in line with the bone's long axis at 13 times 10-3 microstrain per second. When walking the largest deformation occurred prior to 'toe off'; compression was then the larger principal strain about minus 400 microstrain applied at 37 degrees to the bone's long axis at minus 4 times 10-3 microstrain per second.

Mackay EH, Banks J, Sykes B, Lee G. Structural basis for the changing physical properties of human pulmonary vessels with age. Thorax. 1978;33:335–344. 
Contrary to expectation, there was a steady fall in medial collagen content with increasing age in arteries and veins. The thickness of the vessel media did not change significantly with age. The pulmonary artery and vein strips were less extensible in the older age groups, the main change occurring in the elastic phase of the vascular stress/strain curves. It is suggested that changes in the elastic tissue at a molecular and lamellar level are responsible for the increasing stiffness of pulmonary vessels rather than changes in the medial collagen content.

1980s

Plank L, James J, Wagenvoort CA.  Caliber and elastin content of the pulmonary trunk.  Arch Pathol Lab Med.  1980;104:238-241.

Bentley R, Meganathan R.  Biosynthesis of vitamin K (menaquinone) in bacteria.  Microbiol Rev.  1982 Sep;46(3):241-80. 

Price PA, Urist MR, Otawara Y.  Matrix Gla protein, a new γ‐carboxyglutamic acid-containing protein which is associated with the organic matrix of bone.  Biochemical and Biophysical Research Communications.  1983;117(3):765-771.
A new protein has been isolated from CaCl2/urea extracts of demineralized bovine bone matrix. This protein has five to six residues of the vitamin K-dependent amino acid, gamma-carboxyglutamic acid (Gla), and we have accordingly designated it matrix Gla protein. 

Hosoda Y, Kawano K, Yamasawa F, Ishii T, Shibata T, Inayama S. Age-dependent changes of collagen and elastin content in human aorta and pulmonary artery. Angiology. 1984;35:615–621. 
Elastin content of the pulmonary artery increases with age in the adult. This paper seems to be the first report of simultaneous estimation of collagen and elastin content of both the aorta and the pulmonary artery.

Andersen P, Saltin B. Maximal perfusion of skeletal muscle in man. J Physiol. 1985;366:233–249. 
Five subjects exercised with the knee extensor of one limb at work loads ranging from 10 to 60 W. Measurements of pulmonary oxygen uptake, heart rate, leg blood flow, blood pressure and femoral arterial-venous differences for oxygen and lactate were made between 5 and 10 min of the exercise.  It is concluded that muscle blood flow is closely related to the oxygen demand of the exercising muscles. The hyperaemia at low work intensities is due to vasodilatation, and an elevated mean arterial blood pressure only contributes to the linear increase in flow at high work rates. The magnitude of perfusion observed during intense exercise indicates that the vascular bed of skeletal muscle is not a limiting factor for oxygen transport.

 Green S, Askew C. Vo2peak is an acceptable estimate of cardiorespiratory fitness but not vo2maxJ Appl Physiol. 1985;125: 229–232.

Jacobs RA, Rasmussen P, Siebenmann C, Diaz V, Gassmann M, Pesta D, et al.  Determinants of time trial performance and maximal incremental exercise in highly trained endurance athletes.  J Apply Physiol.  1985;111:1422-1430.
Human endurance performance can be predicted from maximal oxygen consumption (Vo2 max), lactate threshold and exercise efficiency.  This study sought to identify more specific measurements that explain the range of performance among athletes. Out of 10 principal factors they concluded that skeletal muscle oxidative capacity is the primary predictor of time trial performance in highly trained cyclists.  The strongest predictor for maximal incremental power output is body hemoglobin mass, and overall exercise performance correlates most strongly to measures regarding the capability for oxygen transport – Vo2 max and body hemoglobin mass in addition to measures of oxygen utilization, oxidative phosphorylation and electron transport system capacities in the skeletal muscle. 

Jansson E, Kaijser L. Substrate utilization and enzymes in skeletal muscle of extremely endurance-trained menJ Appl Physiol.  1985;62:999–1005. 
Substrate utilization during exercise at 65% of maximal O2 uptake (VO2 max) and biochemical characteristics of vastus lateralis were compared between five endurance-trained (T) and five untrained subjects (U). The oxidative enzyme activities were 100% greater in T than in U, and VO2 max was 50% higher. A greater proportion of ATP regeneration occurred through oxidative processes in T than in U (smaller leg lactate release and smaller muscle lactate accumulation). The respiratory exchange ratio together with the local leg respiratory quotient indicated a greater contribution of fat to oxidative metabolism in T than U (53 vs. 33%). No difference, however, in the ratio of plasma free fatty acid extraction to O2 extraction by the working legs was found between T and U. Thus it could be calculated that a greater fraction of fat oxidation would have been covered by intramuscular triglycerides in T than in U (34 vs. 15%, P less than 0.05). T in comparison to U were further characterized by a smaller glycogen breakdown and a smaller glucose uptake, which may have been one contributing factor that prevented the blood glucose level from falling in T. 

Lanyon LE, Rubin CT.  Static vs dynamic loads as an influence on bone remodelling.  J Biomechanics.  1984;17(2):897-905. 

Poole DC, Jones AM. Measurement of the maximum oxygen uptake vo2max: VO2peak is no longer acceptableJ Appl Physiol.  1985;122: 997–1002.
The maximum rate of O2 uptake (i.e., V̇o2max), as measured during large muscle mass exercise such as cycling or running, is widely considered to be the gold standard measurement of integrated cardiopulmonary-muscle oxidative function. Although this is more suitable for clinical and experimental investigations and enables measurement of the gas exchange threshold, exercise efficiency, and V̇o2 kinetics, a V̇o2-work rate plateau is not an obligatory outcome. This shortcoming has led to investigators resorting to so-called secondary criteria such as respiratory exchange ratio, maximal heart rate, and/or maximal blood lactate concentration, the acceptable values of which may be selected arbitrarily and result in grossly inaccurate V̇o2max estimation. This CORP presents the rationale for incorporation of a second, constant work rate test performed at ~110% of the work rate achieved on the initial ramp test to resolve the classic V̇o2-work rate plateau that is the unambiguous validation of V̇o2max The broad utility of this procedure has been established for children, adults of varying fitness, obese individuals, and patient populations. 

Rønnestad BR, Hansen J, Stensløkken L, Joyner MJ, Lundby C. Case studies in physiology: temporal changes in determinants of aerobic performance in individual going from alpine skier to world junior champion time trial cyclistJ Appl Physio.  1985;127:306–311.
This paper reports temporal changes in physiological measurements of exercise performance in a young man transitioning from alpine skiing until he became a world junior champion time trial cyclist after only 3 years of bike-specific training. At the time he became World Champion he also achieved among the highest reported maximal oxygen uptake (V̇o2max) value, 96.7 ml·min-1·kg-1, or 7,397 ml/min in absolute terms at 76.5 kg, which had increased by 29.6% from 74.6 ml·min-1·kg-1 pre-bike-specific training. After 15 months with almost no structured exercise training, V̇o2max returned to 77.0 mL·min-1·kg-1 and was similar to the value reported before specific bike training, albeit with absolute term (6,205 ml/min) still being 11.3% higher. Part of the explanation for his athletic achievements is likely also related to the up to 20.9% improvement in blood lactate levels (Power@4 mmol/l (W). This study shows that very high V̇o2max values (>70 ml·min-1·kg-1) can be found in individuals not previously specializing in aerobic training and that values of >90 ml·min-1·kg-1, as well as a cycling world junior champion title, can be achieved in such individuals with just 3 years of dedicated exercise training. 

Smuder AJ, Kavazis AN, Min K, Powers SK. 2011. Exercise protects against doxorubicin-induced markers of autophagy signaling in skeletal muscleJ Appl Physiol.  1985;111 1190–1198. 

Hauschka PV. Osteocalcin: the vitamin K-dependent Ca2+-binding protein of bone matrix. Haemostasis. 1986;16(3–4):258–272. 
Osteocalcin appears to be a highly specific osteoblastic marker produced during bone formation, and is rapidly becoming a clinically important diagnostic parameter of bone pathology. This article reviews recent advances in the understanding of osteocalcin.

Rowell LB, Saltin B, Kiens B, Christensen NJ. Is peak quadriceps blood flow in humans even higher during exercise with hypoxemia? Am J Physiol Heart Circ Physiol. 1986;251:H1038–H1044. 

Simon J, Young JL, Blood DK, Segal KR, Case RB, Gutin B. Plasma lactate and ventilation thresholds in trained and untrained cyclistsJ Appl Physiol.  1986;60: 777–781.
Six trained male cyclists and six untrained sedentary men were studied to determine whether the plasma lactate threshold (PLT) and ventilation threshold (VT) occur at the same work rate in both fit and unfit populations. The PLT was determined from a marked increase in plasma lactate concentration ([La]) and VT from a nonlinear increase in expired minute ventilation (VE) during incremental leg-cycling tests; work rate was increased 30 W every 2 min until volitional exhaustion. The trained subjects' mean VO2 max (63.8 ml O2 X kg-1 X min-1) and VT (65.8% VO2 max) were significantly higher than the untrained subjects' mean VO2max (35.5 ml O2 X kg-1 X min-1) and VT (51.4% VO2 max). The trained subjects' mean PLT (68.8% VO2 max) and VT did not differ significantly, but the untrained subjects' mean PLT (61.6% VO2 max) was significantly higher than their VT. The trained subjects' mean peak [La] (10.5 mmol X l-1) did not differ significantly from the untrained subjects' mean peak [La] (11.5 mmol X l-1). However, the time of appearance of the peak [La] during passive recovery was inversely related to VO2 max. These results suggest that variance in lactate diffusion and/or removal processes between the trained and untrained subjects may account in part for the different relationships between the VT and PLT in each population.

Fraser JD, Price PA.  Lung, heart, and kidney express high levels of mRNA for the vitamin K-dependent matrix Gla protein. Implications for the possible functions of matrix Gla protein and for the tissue distribution of the gamma-carboxylase.  J Biol Chem.  1988;263-11033-11036.
We have used cDNA probes for two small vitamin K-dependent bone matrix proteins, bone Gla protein (BGP) and matrix Gla protein (MGP), to evaluate the possibility that either of these proteins might be synthesized by the various soft tissues previously shown to have gamma-carboxylase activity. BGP mRNA was found in bone but not in any of the soft tissues tested, a result which reinforces the view that plasma BGP is a specific marker for bone metabolism. In contrast, MGP mRNA was found in all rat tissues examined. Lung and heart have 10-fold higher levels of MGP mRNA than bone, and kidney has a 5-fold higher level. Despite the high levels of MGP mRNA in heart and kidney, these tissues contain 40-500-fold lower concentrations of MGP protein than bone. In each tissue, MGP was found in discrete tissue-specific cell types. In most of the soft tissues tested, MGP is the first well characterized substrate for the vitamin K-dependent carboxylase found to be synthesized. The exceptionally broad tissue distribution for MGP synthesis demonstrates that the function of MGP is not specific to connective tissues. 

Hauschka PV, Lian JB, Cole DE, et al. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev. 1989;69:990–1047.

1990s

Mercer RR, Crapo JD.  Spatial distribution of collagen and elastin fibers in the lungs.  J Applied Psych.  1990 Aug 1;69(2):756-65.
Surface tension forces acting on the thin-wall alveolar septa and the collagen-elastin fiber network are major factors in lung micromechanics. Quantitative serial section analysis and morphometric evaluations of planar sections were used to determine the spatial location of collagen and elastin fibers in Sprague-Dawley rat and normal human lung samples. A large concentration of connective tissue fibers was located in the alveolar duct wall in both species. For rats, the tissue densities of collagen and elastin fibers located within 10 microns of an alveolar duct were 13 and 9%, respectively. In human lung samples, the tissue densities of collagen and elastin fibers within 20 microns of an alveolar duct were 18 and 16%, respectively. In both species, bands of elastin fibers formed a continuous ring around each alveolar mouth. In human lungs, elastin fibers were found to penetrate significantly deeper into alveolar septal walls than they did in rat lungs. The concentration of connective tissue elements in the alveolar duct walls of both species is consistent with their proposed roles as the principal load-bearing elements of the lung parenchyma.

Akedo Y. Hosoi T, Inoue S. Ikegami A. Mizuno Y. Kaneki M. et al.  K2 modulates proliferation and function of osteo-blastic cells in vitro. Biochem Biophys Res Commun1992;187:814–820.
A human osteosarcoma cell line, HOS TE85 cells, and a mouse osteoblastic cell line, MC3T3-E1 cells, were cultured for 3 days in a medium containing various concentrations of menaquinone-4 (vitamin K2). As a result, the proliferation of HOS cells was suppressed by vitamin K2 in a dose dependent manner up to 56% and that of MC3T3-E1 cells was suppressed to 84% Warfarin counteracted the effect of vitamin K2 on osteoblastic cell proliferation. Our results show that vitamin K2 modulates proliferation and function of osteoblastic cells by some mechanisms including gamma-carboxylation system. 

Boskey AL, Rimnac CM, Bansal M, Federman M, Lian J, Boyan BD. Effect of short-term hypomagnesemia on the chemical and mechanical properties of rat bone. J Orthop Res1992;10:774–783. 

Davidson JM.  Elastin in the Lung.  In Grasse C et al, editors.  Biochemistry of Pulmonary Emphysema. London:Springer-Verlag. 1992. P. 13-26. 

Szulc P, Chapuy M.C., Meunier P.J., Delmas P.D. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Investig. 1993;91:1769–1774.
It has been previously shown that the level of circulating undercarboxylated osteocalcin (ucOC) is elevated in elderly women in comparison with young, healthy, premenopausal ones. To understand the mechanism of the increase in the ucOC in the elderly and to assess its potential consequences on bone fragility, we have measured ucOC in the sera of 195 elderly institutionalized women 70-101 yr of age. In 45 women (23%) serum ucOC was above the upper limit of the normal range for young women and the level of ucOC was negatively correlated with vitamin D even after excluding the effect of age, parathyroid hormone (PTH), and creatinine by partial correlation.  During an 18-mo follow-up the risk of hip fracture was increased in women with elevated ucOC. In conclusion, the increase in ucOC in the elderly reflects not only some degree of vitamin K deficiency but also their poor vitamin D status, suggesting that vitamin D may be important, either directly or indirectly through its effect on bone turnover, for achieving a normal gamma-carboxylation of OC. The ucOC, but not conventional calcium metabolism parameters, predicts the subsequent risk of hip fracture, suggesting that serum ucOC reflects some changes in bone matrix associated with increased fragility. 

Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD. Circulating levels of vitamins K1 and K2 decreased in elderly women with hip fracture. J Bone Miner Res1993;8(10):1241–1245.
We measured the serum levels of phylloquinone (vitamin K1) and of the menaquinones, MK-7 and MK-8, in a group of 51 women with a mean age of 81 years who were studied within a few hours after a hip fracture. A group of 38 healthy age-matched women randomly chosen from the same population served as controls. Patients with hip fracture had a marked reduction in serum vitamin K1 and a large number had undetectable levels, especially of MK-8. These data suggest that patients with hip fracture have vitamin K deficiency, an abnormality that could affect bone metabolism through an impairment of the gamma carboxylation of the gla-containing proteins of bone. 

Naylor JR, Young FB.  A general population survey of rest cramps.  Age Ageing.  1994;23:418-420.
The overall prevalence of rest cramps in the survey population was 37%. The symptom was more prevalent in older subjects. Rest cramps were most commonly experienced in the muscles of the leg, in 83% of the 86 cramp sufferers. Symptoms were usually present at night (73%). On average cramp episodes lasted for 9 min (95%CI 6.7-11.2). Most cramps sufferers experienced symptoms infrequently, but 40% had cramp episodes more than three times per week and 6% complained of at least one episode per day or night. Twenty-one per cent of cramp sufferers described their symptoms as very distressing. 

Sun D, Huang A, Koller A, Kaley G. Short-term daily exercise activity enhances endothelial NO synthesis in skeletal muscle arterioles of rats. J Appl Physiol. 1994;76:2241–7. 

Barrientos A, Casademont J, Rotig A, Miro O, Urbano-Marquez A, Rustin P, Cardellach F. Absence of relationship between the level of electron transport chain activities and aging in human skeletal muscleBiochem Biophys Res Commun. 1996;229: 536–539.
We investigated the relationship between age and respiratory chain function of skeletal muscle mitochondria in 132 control individuals (15 to 95 years old). They found a significant inverse correlation between age and oxygen uptake linked to substrate oxidation (succinate, glutamate-malate or ascorbate-TMPD). However, this significance disappeared after including physical activity and tobacco consumption as confounding variables. Similarly, the activity of respiratory chain complexes individually measured did not decline with age. It therefore appears that respiratory chain activity in human skeletal muscle mitochondria is substantially undamaged during the aging process.

Brierley EJ, Johnson MA, James OF, Turnbull DM. Effects of physical activity and age on mitochondrial functionQJM. 1996;89:251–258.
It has been proposed that aging results from the accumulation of mitochondrial DNA mutations which interfere with respiratory chain ATP production. Insufficient ATP production impairs cell function, and tissue dysfunction ensues, leading to morbidity, decline and eventually death.  We hypothesized that an age-related reduction in physical activity could be an important factor in this decline and thus studied the influence of chronological age on muscle mitochondria in subjects matched for levels of physical activity. In this carefully selected group, there was little correlation between oxidative metabolism and age. Our results suggest that reduced physical activity is a major contribution to the decline in mitochondrial oxidations during ageing. Physical activity ameliorates and may even mask mitochondrial 'ageing' in muscle.

Hara K, Akiyama Y, Nakamura T, Murota S, & Morita I. The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chainBone.  1995;16(2):179–184.

Sharkey NA, Ferris L, Smith TS, Matthews DK.  Strain and loading of the second metatarsal during heel-lift. J Bone Joint Surg. 1995;77(7):1050–1057.
Metatarsal stress fractures occur in military recruits after long marches and in athletes after episodes of overtraining involving running or jumping. It has been demonstrated that contraction of the plantar flexors of the toes helps to counteract the moments placed on the metatarsals by body weight. It is possible that physiological fatigue due to strenuous or repetitive exercise reduces the rate and force of contraction of the plantar flexors, thereby increasing metatarsal strain per cycle, and that this mechanism is the primary cause of stress fractures of these bones. To test the hypothesis that fatigue of the plantar flexors causes increased metatarsal loading, thereby predisposing these bones to stress fracture, we measured metatarsal strains in nine fresh cadaveric feet with use of an apparatus that simulated physiological loading due to body weight as well as contraction of the plantar flexors. Each foot was loaded to 750 newtons of ground-reaction force by simulated contraction of the triceps surae, and strains were recorded in the mid-part of the shaft of the second metatarsal. Tests were repeated with use of simulated activity of different combinations of the flexor digitorum longus, flexor hallucis longus, peroneus brevis, peroneus longus, and tibialis posterior muscles. In situ bending moments and axial loads subsequently were derived for each configuration. Dorsal strain was significantly reduced by simulated contraction of the flexor hallucis longus. Plantar-dorsal bending was significantly reduced by simulated contraction of the flexor digitorum longus.

Ducy P, Desbois C, Boyce B, et al. Increased bone formation in osteocalcin-deficient mice. Nature. 1996;382:448–452.
Vertebrates constantly remodel bone. The resorption of preexisting bone by osteoclasts and the formation of new bone by osteoblasts is strictly coordinated to maintain bone mass within defined limits. A few molecular determinants of bone remodeling that affect osteoclast activity have been characterized, but the molecular determinants of osteoblast activity are unknown. To investigate the role of osteocalcin, the most abundant osteoblast-specific non-collagenous protein, we have generated osteocalcin-deficient mice. These mice develop a phenotype marked by higher bone mass and bones of improved functional quality. Histomorphometric studies done before and after ovariectomy showed that the absence of osteocalcin leads to an increase in bone formation without impairing bone resorption. To our knowledge, this study provides the first evidence that osteocalcin is a determinant of bone formation. 

Kameda T, Miyazawa K, Mori Y, Yuasa T, Shiokawa M, Nakamaru , et al.  Vitamin K2 inhibits osteoclastic bone resorption by inducing osteoclast apoptosis. Biochem Biophys Res Commun1996;220:515–519.
In contrast to vitamin K1(VK1), vitamin K2(VK2) inhibited osteoclastic bone resorption by unfractionated bone cells and isolated osteoclasts. To investigate the mechanism of inhibition of osteoclastic bone resorption by VK2, we examined the effect of this vitamin on osteoclast apoptosis.  In unfractionated bone cells and isolated osteoclasts on dentin slices, we first demonstrated that VK2 induced osteoclast apoptosis, but VK1 did not. These results suggest the possibility that VK2 inhibits osteoclastic bone resorption by targeting osteoclasts to undergo apoptosis, which leads to cell death. 

Spina, R. J. et al. Mitochondrial enzymes increase in muscle in response to 7-10 days of cycle exercise. J App. Physiol. 1996;80:2250–2254.
Endurance exercise training induces a significant increase in the respiratory capacity of skeletal muscle. This is reflected by a training-induced increase in mitochondrial enzyme activity. One consequence of this adaptation is that there is a decreased reliance on carbohydrate utilization with a concomitant increase in fat utilization, resulting in an improvement in endurance capacity. Recently it has been reported that 7-14 days of cycle ergometer exercise training does not induce an increase in mitochondrial enzyme levels in skeletal muscle but, nevertheless, results in smaller decreases in phosphocreatine and glycogen and smaller increases in Pi and lactate in muscle in response to the same exercise after compared to before training. The present study was performed to reevaluate the effect of short-term training (7-10 days) on mitochondrial enzymes in skeletal muscle of humans. Twelve subjects [6 men and 6 women, 27 +/- 5 (SE) yr old] underwent 7 (n = 5) or 10 days (n = 7) of cycle ergometer exercise for 2h/day at 60-70% of peak O2 consumption. Peak O2 consumption was increased by 9% in response to training. Blood lactate levels were lower at the same absolute work rates after than before training. The activities of citrate synthase, beta-hydroxyacyl-CoA dehydrogenase, mitochondrial thiolase, and carnitine acetyltransferase were increased by approximately 30% in response to training. The results of the present study provide evidence that in humans, as in rats, the adaptive increase in mitochondrial enzymes in skeletal muscle occurs fairly rapidly in response to exercise training.

Wagner PD.  Determinants of maximal oxygen transport and utilization.  Annu Rev Physiol.  1996;58:21-50.
Maximal VO2 (VO2max) has mostly been the province of exercise physiologists wishing to provide a measure of athletic potential or to characterize subjects in exercise-related research. It is also used clinically to determine a patient's exercise capacity. More recently, it has been recognized that the study of VO2max can provide fundamental insight into O2 transport at all points between inspired air and muscle mitochondria. This review focuses on understanding how VO2max is set and concludes that the more athletic one is, the more VO2max is sensitive to O2 transport conductances in the lungs, circulation, and skeletal muscle. These transport conductances form an integrated system, all components interacting to define VO2max. A particularly important component is diffusive conductance in muscle. This appears to be abnormal in chronic conditions such as obstructive pulmonary disease and heart and renal failure and may well explain why correction of central cardiovascular defects in O2 transport in such patients fails to restore exercise capacity. 

Burr DB.  Muscle strength, bone mass, and age-related bone loss.  JBMR.  1997 Oct;12(10):1547-1551.
The effects of disuse or conversely, of elevated physical activity on muscle strength and bone mass are well known. Disuse causes muscle wasting and bone loss; physical activity increases muscle strength and bone mass. The association between muscle strength and bone mass is therefore clearly established, although neither the dominant effect of muscle on bone mass, nor the cause and effect relationship is established by these simple correlations alone.  More recently, this has been demonstrated using experimental data from implanted hip prostheses which shows that >70% of the bending moments on a bone are transmitted by muscle force rather than body weight.  Based on the predictions of theoretical analyses and computational models, and based on supporting experimental data, it is well established that forces applied to bone are primarily the result of muscular contraction. 

Kanai T, Takagi T, Masuhiro K, Nakamura M, Iwata M, Saji F. Serum vitamin K level and bone mineral density in post-menopausal women. Int J Gynaecol Obstet. 1997;56(1):25–30.
Vitamin K is known to influence bone metabolism by facilitating the synthesis of osteocalcin. The bone mineral density decreases drastically after menopause. We investigated the relationship of bone mineral density, vitamin K levels and other biological parameters of bone metabolism in 71 post-menopausal women, some with reduced bone mineral density and some on hormone replacement therapy.  They found that women with reduced bone mineral density showed lower levels of vitamin K1 and K2 than those with normal bone mineral density. In the other group, the level of osteocalcin decreased but levels of vitamin K showed no increase during HRT. They concluded that the findings suggested that vitamin K was related to post-menopausal bone mineral loss.

Koskolou MD, Calbet JA, Rådegran G, Roach RC. Hypoxia and the cardiovascular response to dynamic knee-extensor exercise. Am J Physiol Heart Circ Physiol. 1997;272:H2655–H2663. 
Hypoxia affects O2 transport and aerobic exercise capacity. In two previous studies, conflicting results have been reported regarding whether O2 delivery to the muscle is increased with hypoxia or whether there is a more efficient O2 extraction to allow for compensation of the decreased O2 availability at submaximal and maximal exercise. To reconcile this discrepancy, we measured limb blood flow (LBF), cardiac output, and O2 uptake during two-legged knee-extensor exercise in eight healthy young men. During submaximal exercise, LBF increased in hypoxia and compensated for the decrement in arterial O2 content. At peak effort, however, our subjects did not achieve a higher cardiac output or LBF. Thus O2 delivery was not maintained and peak power output and leg O2 uptake were reduced proportionately. These data are consistent then with the findings of an increased limb blood flow to compensate for hypoxemia at submaximal exercise, but no such increase occurs at peak effort despite substantial cardiac capacity for an elevation in LBF.

Lu T-W, Taylor SJG, O’Connor JJ, Walker PS.  Influence of muscle activity on the forces in the femur:  an in vivo study.  J Biomech.  1997 Nov-Dec;30(11-12):110-1106.

LuoG, Ducy, P, McKee, MD, et al. (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386:78–81.
Calcification of the extracellular matrix (ECM) can be physiological or pathological. Physiological calcification occurs in bone when the soft ECM is converted into a rigid material capable of sustaining mechanical force; pathological calcification can occur in arteries and cartilage and other soft tissues. No molecular determinant regulating ECM calcification has yet been identified. A candidate molecule is matrix GLA protein (Mgp), a mineral-binding ECM protein synthesized by vascular smooth-muscle cells and chondrocytes, two cell types that produce an uncalcified ECM. Mice that lack Mgp develop to term but die within two months as a result of arterial calcification which leads to blood-vessel rupture. Mgp-deficient mice additionally exhibit inappropriate calcification of various cartilages, including the growth plate, which eventually leads to short stature, osteopenia and fractures. These results indicate that ECM calcification must be actively inhibited in soft tissues. To our knowledge, Mgp is the first inhibitor of calcification of arteries and cartilage to be characterized in vivo.

Mariani TJ, Sandefur S, Pierce RA.  Elastin in lung development.  Exp Lung Res.  1997;23(2):131-145.
Elastin is a critical component of the lung interstitium, providing the property of recoil to the vascular, conducting airway, and terminal airspace compartments of the lung. Elastic fibers are produced primarily during late fetal and neonatal stages of development. The factors and molecular mechanisms regulating the expression of tropoelastin are currently under investigation. The onset and inductive phase of tropoelastin expression are characterized by increased transcription of the tropoelastin gene. Glucocorticoids accelerate this induction in fetal rats during the canalicular stage of lung development. Many additional factors regulate tropoelastin expression in cultured lung fibroblasts and vascular smooth muscle cells, but the in vivo roles of such mediators are still under investigation. Elastin metabolism is altered in several experimental models of bronchopulmonary dysplasia, suggesting that normal elastin production and deposition is necessary for proper development of alveoli.

Noakes TD. 1996 J.B. Wolffe Memorial Lecture. Challenging beliefs: ex Africa semper aliquid novi. Med Sci Sports Exerc. 1997;29:571–590. 
An unusual feature of the exercise sciences is that certain core beliefs are based on an historical physiological model that, it will be argued, has somehow escaped modern, disinterested intellectual scrutiny. This particular model holds that the cardiovascular system has a limited capacity to supply oxygen to the active muscles, especially during maximal exercise. As a result, skeletal muscle oxygen demand outstrips supply causing the development of skeletal muscle hypoxia or even anaerobiosis during vigorous exercise. This hypoxia stimulates the onset of lactate production at the "anaerobic," "lactate," or ventilation thresholds and initiates biochemical processes that terminate maximal exercise. The model further predicts that the important effect of training is to increase oxygen delivery to and oxygen utilization by the active muscles during exercise. Thus, adaptations that reduce skeletal muscle anaerobiosis during exercise explain all the physiological, biochemical, and functional changes that develop with training. The historical basis for this model is the original research of Nobel Laureate A. V. Hill which was interpreted as evidence that oxygen consumption "plateaus" during progressive exercise to exhaustion, indicating the development of skeletal muscle anaerobiosis. There is no definitive evidence that supports this theory. The finding that exercise performance can improve and metabolism alter, before there are measurable skeletal muscle mitochondrial adaptations could indicate that variables unrelated to oxygen use by muscle might explain some, if not all, training-induced changes. To accommodate these uncertainties, an alternate physiological model is proposed in which skeletal muscle contractile activity is regulated by neural, and peripheral chemical, regulators that act to prevent the development of organ damage or even death during exercise in both health and disease and under demanding environmental conditions. The challenge for future generations of exercise physiologists is to identify how the body anticipates the possibility of organ damage and evokes the appropriate control mechanism(s) at the appropriate instant. 

Seibel MJ, Robins SP, Bilezikian JP. Serum undercarboxylated osteocalcin and the risk of hip fracture. J Clin Endorcino Metab. 1997;82:717–718.
The discovery of osteocalcin (bone Gla protein, BGP) in the mid-seventies by Price and coworkers (1) ushered in a period of unprecedented interest in markers of bone metabolism that continues to this day. A product almost exclusively of mature, active osteoblasts, the protein containing 49 amino acids is a secretory cleavage product of a larger intracellular precursor molecule. Transcription of the osteocalcin gene, located on chromosome 1, is regulated by 1, 25-dihydroxyvitamin D, estrogens, glucocorticoids, and other molecules. Posttranslational modification of osteocalcin occurs through the vitamin K-dependent gamma-carboxylation of three glutamate molecules in positions 17, 21, and 24 of the human protein. Vitamin D may also have a role in this posttranslational process (2). Gamma-carboxylation of the nascent protein is largely responsible for its calcium binding properties. In the course of its secretion into the milieu of bone, osteocalcin also gains access to the circulation where it can be measured. Although the exact role of osteocalcin in bone metabolism remains obscure, this circulating protein is a focus of great interest as a marker of bone formation and turnover (3).The relevance of vitamin K deficiency to possible abnormalities in osteocalcin function, by virtue of undercarboxylation, was highlighted by Price et al.(4), who demonstrated that the skeleton was sensitive to deficiency in this vitamin. Clinical studies showed subsequently that vitamin K deficiency, and other factors such as aging, may in fact lead to an impairment in the carboxylation of osteocalcin, resulting in a disproportionate increase in the undercarboxylated form of osteocalcin (ucOC) in the circulation (5, 6). Vitamin K2 levels have been shown by Hodges et al.(7) to be lower in women with osteoporotic fractures than in healthy individuals. Szulc et al. showed that in elderly, institutionalized women followed for 18–36 months, increased serum levels of ucOC were predictive of hip fracture (8–9). These latter results, however, might have been indicative merely of an association between poor nutritional status and hip fracture risk among institutionalized subjects and not necessarily a general biological mechanism that could be relevant to a more representative sampling of the population. 

Vergnaud P, Garnero P, Meunier P., Bréart G, Kamihagi K, Delmas PD. Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: The EPIDOS study. J Clin Endocrinol Metab. 1997;82:719–724.
Increased levels of circulating undercarboxylated osteocalcin (ucOC), measured indirectly with the hydroxyapatite (HAP) binding assay, have been shown to predict hip fracture risk in a small group of elderly institutionalized women. The aim of this study was to confirm these findings in a prospective cohort study (EPIDOS prospective study) of 7598 healthy, independently living women over 75 years of age. We found that increased levels of ucOC measured by ELISA were associated with increased hip fracture risk with an odds ratio (OR) of 1.9 (95% confidence interval, 1.2-3.0), and the ELISA had a greater sensitivity than the HAP assay. Using this new ELISA, we found that ucOC, but not total OC, predicts hip fracture risk independently of femoral neck BMD in elderly women drawn from the general population. Thus, ucOC measurement could be combined with bone mass determination to improve the assessment of hip fracture risk in elderly women. 

Wu SM, Stafford DW, Frazier LD, Fu YY, High KA, Chu K, Sanchez-Vega B, et al.  Genomic sequence and transcription start site for human gamma-glutamyl carboxylase.  Blood.  1997 Jun 1;89(11):4058-62.
The human gene for gamma-glutamyl carboxylase is 13 kb in length and contains 15 exons. Transcription starts at a cytosine 217 base pair upstream of the first codon. There are two major transcripts in all tissues examined. They are distinguished by the presence of an Alu sequence in the 3' nontranslated end of the longer species. Relative mRNA levels for 12 bovine tissues are presented. 

Cräciun AM, Wolf J, Knapen MHJ, Brouns F, Vermeer C.   Improved bone metabolism in female elite athletes after vitamin K supplementation. Int Sports Med. 1998; 19: 479-484.
In female elite athletes strenuous exercise may result in hypoestrogenism and amenorrhoea. As a consequence a low peak bone mass and rapid bone loss are often seen in relatively young athletes. In postmenopausal women, increased intake of vitamin K may result in an increase of serum markers for bone formation, a decrease of urinary markers for bone resorption, and a decrease in urinary calcium loss. In the present paper we report an intervention study among eight female athletes, four of whom had been amenorrhoeic for more than one year, whereas the others had been using oral contraceptives All participants received vitamin K supplementation (10 mg/day) during one month, and various bone markers were measured before and after treatment. At baseline the athletes not using oral contraceptives were biochemically vitamin K-deficient as deduced from the calcium binding capacity of the circulating bone protein osteocalcin. In all subjects increased vitamin K intake was associated with an increased calcium-binding capacity of osteocalcin. In the low-estrogen group vitamin K supplementation induced a 15-20% increase of bone formation markers and a parallel 20-25 % decrease of bone resorption markers. This results could suggest an improved balance between bone formation and resorption. 

Delp MD, Laughlin MH. Regulation of skeletal muscle perfusion during exercise. Acta Physiol Scand1998;162:411–419. 
For exercise to be sustained, it is essential that adequate blood flow be provided to skeletal muscle. The local vascular control mechanisms involved in regulating muscle perfusion during exercise include metabolic control, endothelium-mediated control, propagated responses, myogenic control, and the muscle pump. The primary determinant of muscle perfusion during sustained exercise is the metabolic rate of the muscle. Metabolites from contracting muscle diffuse to resistance arterioles and act directly to induce vasodilation, or indirectly to inhibit noradrenaline release from sympathetic nerve endings and oppose alpha-adrenoreceptor-mediated vasoconstriction. The vascular endothelium also releases vasodilator substances (e.g., prostacyclin and nitric oxide) that are prominent in establishing basal vascular tone, but these substances do not appear to contribute to the exercise hyperemia in muscle. Endothelial and smooth muscle cells may also be involved in propagating vasodilator signals along arterioles to parent and daughter vessels. The rhythmic propulsion of blood from skeletal muscle veins facilitates venous return to the heart and muscle perfusion. It appears that the primary determinants of sustained exercise hyperemia in skeletal muscle are metabolic vasodilation and increased vascular conductance via the muscle pump. Additionally, sympathetic neural control is important in regulating muscle blood flow during exercise.

Proudfoot D, Shanahan CM, Weissberg PL.  Vascular calcification:  new insights into an old problem.  J of Path.  1998 May;185(1):1-3.
This review covers the pathology of intimal and medial vascular calcification and discusses the molecular mechanisms of vascular calcification in light of recent molecular biology and molecular genetic studies.

Wisloff U, Helgerud J, Hoff J. Strength and endurance of elite soccer players. Med Sci Sports Exerc. 1998;30:462–467.
Maximal VO2 (VO2max) has mostly been the province of exercise physiologists wishing to provide a measure of athletic potential or to characterize subjects in exercise-related research. It is also used clinically to determine a patient's exercise capacity. More recently, it has been recognized that the study of VO2max can provide fundamental insight into O2 transport at all points between inspired air and muscle mitochondria. This review focuses on understanding how VO2max is set and concludes that the more athletic one is, the more VO2max is sensitive to O2 transport conductances in the lungs, circulation, and skeletal muscle. These transport conductances form an integrated system, all components interacting to define VO2max. A particularly important component is diffusive conductance in muscle. This appears to be abnormal in chronic conditions such as obstructive pulmonary disease and heart and renal failure and may well explain why correction of central cardiovascular defects in O2 transport in such patients fails to restore exercise capacity. 

Abdulla A, Jones PW, Pearce VR.  Leg cramps in the elderly:  prevalence, drug and disease associations.  IJCP. 1999;53(7);494-496.
To determine the prevalence of leg cramps in elderly outpatients and their association any underlying diseases and concomitant drug intake, we conducted a cross-sectional study using an in-depth questionnaire. A total of 365 patients aged 65 years and over (mean 78.5 years) attending our outpatient clinic participated in the study. The prevalence of leg cramps was 50%. Cramps were commoner in females (56%) than in males (40%). Although reported to occur anytime throughout the 24 hours, cramps were most prevalent at night (62%). In many patients, leg cramps were a long-standing complaint: 20% had been suffering with them for more than 10 years, whereas only 9% of patients reported them first starting within the last six months. Only 73 (40%) sufferers had informed their practitioner; of these, 39 (53%) received treatment, of whom 26 gained benefit. Leg cramps were strongly associated with peripheral vascular disease, arthritis, and female gender. Heart failure, hypertension, diabetes mellitus and stroke were not significantly associated. Except for a causal association with analgesic use, no positive association could be shown with any other class of drugs, including diuretics. 

Beere PA, Russell SD, Morey MC, Kitaman DW, Higginbotham MB.  Aerobic exercise training can reverse age-related peripheral circulatory changes in healthy older men.  Circulation. 1999;100:1085-1094.
The age-related decline in maximal oxygen consumption is attenuated by habitual aerobic exercise. The present study assessed the contribution of central and peripheral responses to the age-associated decline in peak oxygen consumption and compared the effect of exercise training in healthy older and younger subjects. Ten older and 13 younger men underwent invasive measurement of central and peripheral cardiovascular responses during an upright, staged cycle exercise test before and after a 3-month period of exercise training with cycle ergometry. At baseline, cardiac output and AV oxygen difference during exercise were significantly lower in older subjects. With training, the older and younger groups increased maximal oxygen consumption by 17.8% and 20.2%, respectively. Peak cardiac output was unchanged in both groups. Systemic AV oxygen difference increased 14.4% in the older group and 14.3% in the younger group and accounted for changes in peak oxygen consumption. Peak leg blood flow increased by 50% in older subjects, whereas the younger group showed no significant change. There was no change in peak leg oxygen extraction in the older group, but in the younger group, leg AV oxygen difference increased by 15.4%. These findings suggest that the age-related decline in maximal oxygen consumption results from a reversible deconditioning effect on the distribution of cardiac output to exercising muscle and an age-related reduction in cardiac output reserve.

Feskanich D, Weber P, Willett WC, Rockett H, Booth SL, Colditz GA. Vitamin K intake and hip fractures. in women: A prospective study. Am J Clin Nutr. 1999;69:74–79.
Vitamin K mediates the γ-carboxylation of osteocalcin. High serum concentrations of undercarboxylated osteocalcin and low serum concentrations of vitamin K are associated with lower bone mineral density and increased risk of hip fracture. We conducted a prospective analysis within the Nurses' Health Study cohort to investigate the hypothesis that high intakes of vitamin K are associated with a lower risk of hip fracture in women.  The data showed that low intakes of vitamin K may increase the risk of hip fracture in women. The data support the suggestion for a reassessment of the vitamin K requirements that are based on bone health and blood coagulation. 

Naik JS, Valic Z, Buckwalter JB, Clifford PS. Rapid vasodilation in response to a brief tetanic muscle contraction. J Appl Physiol. 1999;87:1741Y1746. 

Matsunaga S, Ito H, Sakou T.  The effect of vitamin K and D supplementation on ovariectomy‐induced bone lossCalcified Tissue International. 1999;65(4):285–289.
This study was designed to assess the effect of vitamin K and D supplementation on ovariectomy-induced bone loss. Female Sprague-Dawley rats aged 8-9 months were ovariectomized (OVX) or sham operated and divided into five experimental groups: (1) ovariectomy (OVX), (2) OVX plus vitamin K supplementation, (3) OVX plus vitamin D supplementation, (4) OVX plus vitamin K and vitamin D supplementation, and (5) sham operation. Bone loss in OVX plus vitamin K and vitamin D group was significantly reduced at both 7 and 14 weeks compared with the OVX group. No significant bone loss in OVX plus vitamin K or OVX plus vitamin D groups was found. Our findings indicate that vitamins K and D may have a synergistic effect on reducing bone loss. This is valuable information for the treatment of bone loss in postmenopausal women with osteoporosis.

Wendel DP, Taylor DG, Albertine KH, Keating MT, Li DY.  Impaired distal airway development in mice lacking elastin.  Am J Respira Cell and Mol Biol.  1999;23(3):320-6.  Elastin is a major component of the mammalian lung, predominantly found in the alveoli. Destruction of alveolar elastic fibers is implicated in the pathogenic mechanism of emphysema in adults. These data define a role for elastin in the structure and function of the mature lung and suggest that elastin is important for alveogenesis. To investigate the role of elastin in lung development, we examined mice lacking elastin (Eln-/-). They found that in addition to its role in the structure and function of the mature lung, elastin is essential for pulmonary development and is important for terminal airway branching.

2000s

Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, et al. Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr. 2000;71:1201–1208.
Vitamin K has been associated with bone mineral density (BMD) and risk of hip fracture. The apolipoprotein (apo) E4 allele (APOE*E4) has been associated with bone fracture through a putative effect on vitamin K transport in blood. The objective was to determine the associations between vitamin K intake, apo E genotype, BMD, and hip fracture in a population-based cohort of elderly men and women. The data showed that low vitamin K intakes were associated with an increased incidence of hip fractures in this cohort of elderly men and women. Neither low vitamin K intake nor E4 allele status was associated with low BMD.

Gosker HR, Wouters EF, van der Vusse GJ, Schols AM.  Skeletal muscle dysfunction in chronic obstructive pulmonary disease and chronic heart failure:  underlying mechanisms and therapy perspectives.  Am J Clin Nutr.  2000 May;71(15):1033-47.
Low exercise tolerance has a large influence on health status in chronic obstructive pulmonary disease and chronic heart failure. In addition to primary organ dysfunction, impaired skeletal muscle performance is a strong predictor of low exercise capacity. In both diseases, muscular impairment is multifactorially determined; hypoxia, oxidative stress, disuse, medication, nutritional depletion, and systemic inflammation may contribute to the observed muscle abnormalities and each factor has its own potential for innovative treatment approaches. 

Haapasalo H, Kontulainen S, Sievanen H, Kannus P, Jarvinen M, Vuori I. Exercise-induced bone gain is due to enlargement in bone size without a change in volumetric bone density: a peripheral quantitative computed tomography study of the upper arms of male tennis players. Bone.  2000;27(3):351–357.
Bilateral bone characteristics of the humerus (proximal, shaft, and distal sites) and radius (shaft and distal sites) in 12 former Finnish national-level male tennis players (mean age 30 years) and their 12 age-, height-, and weight-matched controls were measured . In the players, significant side-to-side differences, in favor of the dominant (playing) arm, were found in bone mineral content. In conclusion, the volumetric bone density was almost identical in the dominant and nondominant arms of the players and controls. In other words, the playing arm's extra bone mineral, and thus increased bone strength, was mainly due to increased bone size and not due to a change in volumetric bone density. 

Heaney RP, Abrams S, Dawson-Hughes B, Looker A, Marcus R, Matkovic V, et al. Peak bone mass. Osteoporosis Int. 2000;1:985-1009.  

Janssen I, Heymsfield SB, Baumgartner RN, Ross, R. Estimation of skeletal muscle mass by bioelectrical impedance analysis. J Appl Physiol. 2000;89:465–471. 

Shiraki M, Shiraki Y, Aoki C, Miura M. Vitamin K2 (menatetrenone) effectively prevents fractures. and sustains lumbar bone mineral density in osteoporosis. J Bone Min Res. 2000;15:515–521.
We attempted to investigate whether vitamin K2 (menatetrenone) treatment effectively prevents the incidence of new fractures in osteoporosis. A total of 241 osteoporotic patients were enrolled in a 24-month randomized open label study. The control group (without treatment; n = 121) and the vitamin K2-treated group (n = 120), which received 45 mg/day orally vitamin K2, were followed for lumbar bone mineral density and occurrence of new clinical fractures. Serum level of Glu-osteocalcin (Glu-OC) and menaquinone-4 levels were measured at the end of the follow-up period. These findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures. Furthermore, vitamin K2 treatment enhances gamma-carboxylation of the OC molecule. 

Steensberg A, et al.  Production of interleukin-t in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6.  J Physiol.  2000;529:237-242.
We suggest that IL‐6 produced by skeletal contracting muscle contributes to the maintenance of glucose homeostasis during prolonged exercise. 

Bronner, F. Extracellular and intracellular regulation of calcium homeostasis. Sci World J. 2001;1:919–925.
An organism with an internal skeleton must accumulate calcium while maintaining body fluids at a well-regulated, constant calcium concentration. Neither calcium absorption nor excretion plays a significant regulatory role. Instead, calcium uptake and release by bone surfaces causes plasma calcium to be well regulated. Very rapid shape changes of osteoblasts and osteoclasts, in response to hormonal signals, modulate the available bone surfaces so that plasma calcium can increase when more low-affinity bone calcium binding sites are made available and can decrease when more high-affinity binding sites are exposed. The intracellular free calcium concentration of body cells is also regulated, but because cells are bathed by fluids with vastly higher calcium concentration, their major regulatory mechanism is severe entry restriction. All cells have a calcium-sensing receptor that modulates cell function via its response to extracellular calcium. Fixed intracellular calcium binding sites can, like the body's skeleton, take up and release calcium that has entered the cell, but the principal regulatory tool of the cell is restricted entry. 

Kaneki M, Hedges SJ, Hosoi T, Fujiwara S, Lyons A, Crean S, et al. Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2. Nutrition2001;17:315–321.
We analyzed the relation between the regional difference in natto intake and fracture incidence. A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption in each prefecture throughout Japan. These findings indicate that the large geographic difference in MK-7 levels may be ascribed, at least in part, to natto intake and suggest the possibility that higher MK-7 level resulting from natto consumption may contribute to the relatively lower fracture risk in Japanese women. 

Price PA, Buckley JR, Williamson MK. The amino bisphosphonate ibandronate prevents vitamin D toxicity and inhibits vitamin D-induced calcification of arteries, cartilage, lungs and kidneys in rats. J Nutr. 2001;131:2910–2915.  

Van Loon LJ, Greenhaff PL, Constantin-Teodosiu D, Saris WH, Wagenmakers AJ.  The effects of increasing exercise intensity on muscle fuel utilization in humans.  J Physiol.  2001 Oct 1;536 (Pt 1):295-304. 

Yamaguchi M, Sugimoto E, Hachiya S. Stimulatory effect of menaquinone-7 (vitamin K2) on osteoblastic bone formation in vitro. Mol Cell Biochem. 2001;223:131–137.
This study demonstrates that MK-7 has an anabolic effect on bone tissue and osteoblastic MC3T3-E1 cells in vitro, suggesting that the compound can stimulate osteoblastic bone formation.

Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, et al.  Adaptations of skeletal muscle to exercise: Rapid increase in the transcriptional coactivator PGC-1FASEB J.  2002;16:1879–1886.
Endurance exercise induces increases in mitochondria and the GLUT4 isoform of the glucose transporter in muscle. Although little is known about the mechanisms underlying these adaptations, new information has accumulated regarding how mitochondrial biogenesis and GLUT4 expression are regulated.  One exercise bout resulted in approximately twofold increases in full-length muscle PGC-1 mRNA and PGC-1 protein, which were evident 18 h after exercise. A smaller form of PGC-1 increased after exercise. The exercise induced increases in muscle NRF-1 and NRF-2 that were evident 12 to 18 h after one exercise bout. These findings suggest that increases in PGC-1, NRF-1, and NRF-2 represent key regulatory components of the stimulation of mitochondrial biogenesis by exercise and that PGC-1 mediates the coordinated increases in GLUT4 and mitochondria.

González-Alonso J, Olsen DB, Saltin B. Erythrocyte and the regulation of human skeletal muscle blood flow and oxygen delivery: role of circulating ATP. Circ Res. 2002;91:1046–1055. 

Gundberg CM, Looker AC, Niemen SD, Calvo MS.  Patterns of osteocalcin and bone specific alkaline phosphatase by age, gender, and race or ethnicity.  Bone.  2002 Dec;31(6):703-8.

Kravitz L, Dalleck LC.  Physiological factors limiting endurance exercise capacity. IDEA Health & Fitness Source.  2002;20(4):40-49.
Whether you are a world-class athlete or a recreational runner, your capacity for endurance exercise has similar physiological limitations. Endurance exercise can be defined as the ability to perform cardiovascular exercise, whether it be cross-country skiing, spinning, running, aerobic exercise or swimming, for an extended period of time (Robergs & Roberts 1997). One is limited in this pursuit by a complex integration of multiple physiological functions. Despite the multifaceted nature, endurance exercise is characterized by one simple requirement – the necessity to sustain repeated muscle contraction. This criterion is fulfilled through two basic functions – the ability to consume enough oxygen and an adequate fuel provision. The capacity for oxygen consumption is reliant upon the physiological parameters of maximal oxygen uptake, lactate threshold, and economy of movement in the given activity. Fuel, or food substrate, is supplied mostly through carbohydrates and fats. Hydration levels and genetic factors also play influential roles in the capacity for endurance exercise. This article will review the main physiological mechanisms limiting endurance exercise and performance.

Miyake N, Hoshi K, Sano Y, Kikuchi K, Tadano K, Koshihara Y. 1,25‐Dihydroxyvitamin D3 promotes vitamin K2 metabolism in human osteoblastsOsteoporosis International. 2002;12(8):680–687.  
In the present study, we investigated whether menaquinone-4 (MK-4) was metabolized in human osteoblasts to act as a cofactor of gamma-glutamyl carboxylase. Both conversions of MK-4 to MK-4 2,3-epoxide (epoxide) and epoxide to MK-4 were observed in cell extracts of cultured human osteoblasts. The effect of 1,25(OH)2D3 and warfarin on the vitamin K cycle to cultured osteoblasts were examined. In the present study, it was demonstrated that the vitamin K metabolic cycle functions in human osteoblasts as well as in the liver, the post-translational mechanism, by which 1,25(OH)2D3 caused mineralization in cooperation with vitamin K2 was clarified.

Ozuru R, Sugimoto T, Yamaguchi T, Chihara K.  Time-dependent effects of vitamin K2 (Menatetretone) bone metabolism in postmenopausal women. Endocrine Journal.  2002;49(3):363-370.
We evaluated the effects of vitamin K2 (menatetrenone) treatment (45 mg/day) for 48 weeks on the markers of bone formation and resorption, bone mineral density (BMD), and the incidence of vertebral fractures in 34 Japanese postmenopausal women (aged 48-82 years). Serum levels of both intact osteocalcin (OC) and carboxylated OC (Gla-OC) increased rapidly and significantly within 4 weeks and sustained their high values up to 48 weeks after the treatment, while those of undercarboxylated OC (Glu-OC) decreased reciprocally. These results can be interpreted to suggest that Glu-OC was converted to Gla-OC in vivo. On the other hand, lumbar BMD values showed no significant change and only one subject with a previous vertebral fracture had one newly occurring vertebral fracture. These results indicate that menatetrenone treatment of postmenopausal women constantly elevates bone formation markers as well as converts Glu-OC to Gla-OC. Thus, vitamin K2 treatment may promote bone formation, at least as measured biochemically in these subjects. 

Flück M, Hoppeler H.  Molecular basis of skeletal muscle plasticity-from gene to form and function.  Reviews of Physiology, Biochemistry and Pharmacology. 2003;146:159-216.

Skeletal muscle shows an enormous plasticity to adapt to stimuli such as contractile activity (endurance exercise, electrical stimulation, denervation), loading conditions (resistance training, microgravity), substrate supply (nutritional interventions) or environmental factors (hypoxia). The presented data show that adaptive structural events occur in both muscle fibres (myofibrils, mitochondria) and associated structures (motoneurons and capillaries). Functional adaptations appear to involve alterations in regulatory mechanisms (neuronal, endocrine and intracellular signalling), contractile properties and metabolic capacities. With the appropriate molecular techniques it has been demonstrated over the past 10 years that rapid changes in skeletal muscle mRNA expression occur with exercise in human and rodent species. The accessibility of muscle tissue to biopsies in conjunction with the advent of high-throughput gene expression analysis technology points to skeletal muscle plasticity as a particularly useful paradigm for studying gene regulatory phenomena in humans.

Hoang QQ, Sicheri F, Howard AJ, Yang DS. Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature2003;425(6961):977–980.  

Hoppeler H, Fluck M. Plasticity of skeletal muscle mitochondria:  structure and function.  Med Sci Sports Exerc.  2003;35:95-104. 
Endurance exercise training leads to increases in mitochondrial volume of up to 50% in training interventions of a few weeks in untrained subjects.  Also a shift of substrate metabolism toward a higher reliance on lipids is observed.  A similar increase in lipids without an increase in mitochondrial volume is observed with a high-fat diet.  Strength training has a major impact on muscle myofibrillar volume, however the mitochondrial compartment appears relatively unchanged.  Bedrest and microgravity conditions leads to losses of both myofibrillar and mitochondrial volumme.  Permanent severe hypoxia leads to a loss of muscle mass and muscle oxidative capacity.  The molecular mechanisms that orchestrate the plasticity of skeletal muscle mitochondria are just beginning to be understood.

Huonker M, Schmid A, Schmidt-Trucksass A, Grathwohl D, Keul J. Size and blood flow of central and peripheral arteries in highly trained able-bodied and disabled athletesJ Appl Physiol. 2003;95:685–91.
In a cross-sectional study, central and peripheral arteries were investigated noninvasively in high-performance athletes and in untrained subjects. The diastolic inner vessel diameter (D) of the thoracic and abdominal aorta, the subclavian artery (Sub), and common femoral artery (Fem) were determined by duplex sonography in 18 able-bodied professional tennis players, 34 able-bodied elite road cyclist athletes, 26 athletes with paraplegia, 17 below-knee amputated athletes, and 30 able-bodied, untrained subjects. The study suggests that the size and blood flow volume of the proximal limb arteries are adjusted to the metabolic needs of the corresponding extremity musculature and underscore the impact of exercise training or disuse on the structure and the function of the arterial system. 

Koshihara Y, Hoshi K, Okawara R, Ishibashi H, & Yamamoto S. Vitamin K stimulates osteoblastogenesis and inhibits osteoclastogenesis in human bone marrow cell cultureJournal of Endocrinology. 2003;176(3): 339–348.
Vitamin K might stimulate osteoblastogenesis in bone marrow cells, regulating osteoclastogenesis through the expression of RANKL/ODF more than through that of OPG/OCIF.

Rolland Y, Lauwers-Cances V, Cournot M, et al.  Sarcopenia, calf circumference, and physical function of elderly women:  a cross-sectional study.  J Am Geriatr Soc.  2003;51:1120-1124.

Saminathan R.  Magnesium metabolism and its disorders.  Clin Biochem Rev.  2003;24:47-66. 

Usui T, Maki K, Toki Y, Shibasaki Y, Takanobu H, Takanishi A et al.  Measurement of mechanical strain on mandibular surface with mastication robot:  influence of muscle loading direction and magnitude.  Orthod Craniofac Res.  2003;6 Suppl 1:163-7. 

Aoi W, Naito Y, Takanami Y, Kawai Y, Sakuma K, Ichikawa H, et al. Oxidative stress and delayed-onset muscle damage after exercise. Free Radic Biol Med. 2004;37:480–487.
These results indicate that delayed-onset muscle damage induced by prolonged exercise is partly related to inflammation via phagocyte infiltration caused by ROS and that alpha-tocopherol (an antioxidant) can attenuate such inflammatory changes. 

Braam LA, Hoeks AP, Brouns F, et al. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost 2004; 91: 373–380.
Matrix-Gla Protein (MGP) is a strong inhibitor of vascular calcification, the expression of which is vitamin D dependent. MGP contains five gamma-carboxyglutamic acid (Gla)-residues which are formed in a vitamin K-dependent carboxylation step and which are essential for its function. Hence vascular vitamin K-deficiency will result in undercarboxylated, inactive MGP which is a potential risk factor for calcification. In the present study we describe the effects of vitamin K1 and D supplementation on vascular properties in postmenopausal women, over a three year period. In a randomized placebo-controlled intervention study, 181 postmenopausal women were given either a placebo or a supplement containing minerals and vitamin D (MD-group), or the same supplement with vitamin K1 (MDK-group). The results showed that the elastic properties of the common carotid artery in the MDK-group remained unchanged over the three-year period, but decreased in the MD- and placebo-group. It is concluded that a supplement containing vitamins K1 and D has a beneficial effect on the elastic properties of the arterial vessel wall. 

Geleijnse JM, Vermeer C,  Grobbee DE,  Schurgers LJ,  Knapen HJ, van der Meer IM, et al.   Dietary intake of menaquinone Is associated with a reduced risk of coronary heart disease: The Rotterd Am Study1.  J Nutr.  2004;134:3100–3105.
Vitamin K–dependent proteins, including matrix Gla-protein, have been shown to inhibit vascular calcification. Activation of these proteins via carboxylation depends on the availability of vitamin K. We examined whether dietary intake of phylloquinone (vitamin K-1) and menaquinone (vitamin K-2) were related to aortic calcification and coronary heart disease (CHD) in the population-based Rotterdam Study. The analysis included 4807 subjects with dietary data and no history of myocardial infarction at baseline (1990–1993) who were followed until January 1, 2000. The risk of incident CHD, all-cause mortality, and aortic atherosclerosis was studied in tertiles of energy-adjusted vitamin K intake after adjustment for age, gender, BMI, smoking, diabetes, education, and dietary factors. The relative risk (RR) of CHD mortality was reduced in the mid and upper tertiles of dietary menaquinone compared to the lower tertile Phylloquinone intake was not related to any of the outcomes. These findings suggest that an adequate intake of menaquinone could be important for CHD prevention. 

Heiss C, Hoesel LM, Wehr U, Keller T, Horas U, Meyer C, et al. Vitamin K in combination with other biochemical markers to diagnose osteoporosis. Biomarkers. 2004;9(6):479–488. 

Ivaska KK, Hentunen TA,  Vääräniemi, Yipahkala H, Pettersson K.  Release of intact and fragmented osteocalcin molecules from bone matrix during bone resorption in vitro. Glycobiol Extracell Matrices.  2004;279(18): 18361-18369.
Osteocalcin detected from serum samples is considered a specific marker of osteoblast activity and bone formation rate. However, osteocalcin embedded in bone matrix must also be released during bone resorption. To understand the contribution of each type of bone cell in circulating osteocalcin levels, we used immunoassays detecting different molecular forms of osteocalcin to monitor bone resorption in vitro. In conclusion, osteocalcin is released from the bone matrix during bone resorption as intact molecules and fragments. In addition to the conventional use as a marker of bone formation, osteocalcin can be used as a marker of bone resorption in vitro. Furthermore, bone matrix-derived osteocalcin may contribute to circulating osteocalcin levels, suggesting that serum osteocalcin should be considered as a marker of bone turnover rather than bone formation. 

Karbowski M, Arnoult , Chen H, Chan DC, Smith CL, Youle RJ.  Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. Cell Biol.  2004;164(4):493–499.  

Saunders NR, Tschakovsky ME. Evidence for a rapid vasodilatory contribution to immediate hyperemia in rest-to-mild and mild-to-moderate forearm exercise transitions in humans. J. Appl. Physiol. 2004;97:1143Y1151.

Shimada T, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Min Res. 2004;19:429–435). 

Tschakovsky ME, Rogers AM, Pyke KE, Saunders NR, Glenn N, Lee SJ, Weissgerber T, Dwyer EM. Immediate exercise hyperemia in humans is contraction intensity dependent: evidence for rapid vasodilation. J Appl Physiol. 2004;96:639Y644. 

Välimäki V-V, Alfthan H, Lehmuskallio E, Löyttyniemi E, Sahi T, Stenman U-H, et al.  Vitamin D status as a determinant of peak bone mass in young Finnish men.  J Clin Endo & Metab.  2004;89(1):76-80.
Severe vitamin D deficiency causes rickets, but scarce data are available about the extent to which vitamin D status determines the development of the peak bone mass in young adults. Our aim was to evaluate the prevalence of vitamin D deficiency [serum 25-hydroxyvitamin D (25-OHD) less than the lower limit of the reference range of 20-105 nmol/liter] and the relationship between vitamin D status and peak bone mass among young Finnish men. We conclude that vitamin D deficiency is very common in Finnish young men in the winter, and it may have detrimental effects on the acquisition of maximal peak bone mass. As in Finland vitamin D supplementation to infants is now stopped at the age of 3 yr, it can be asked whether at our latitude it should be continued from that age onward, not for the prevention of rickets, but as prophylaxis for osteoporosis. 

Cartoni R, Leger B, Hock MB, Praz M, Crettenand A, Pich S, et al. Mitofusins 1/2 and ERRα expression are increased in human skeletal muscle after physical exerciseJ Physiol. 2005;567: 349–358. 

Ducher G, Courteix D, Meme S, Magni C, Viala JF, Benhamou CL. Bone geometry in response to long-term tennis playing and its relationship with muscle volume: a quantitative magnetic resonance imaging study in tennis players. Bone. 2005;37:457–66. 
The benefit of impact-loading activity for bone strength depends on whether the additional bone mineral content (BMC) accrued at loaded sites is due to an increased bone size, volumetric bone mineral density (vBMD) or both. Using magnetic resonance imaging (MRI) and dual energy X-ray absorptiometry (DXA), the aim of this study was to characterize the geometric changes of the dominant radius in response to long-term tennis playing and to assess the influence of muscle forces on bone tissue by investigating the muscle-bone relationship. Twenty tennis players (10 men and 10 women, mean age: 23.1+/-4.7 years, with 14.3+/-3.4 years of playing) were recruited. This study showed that the greater bone mineral content induced by long-term tennis playing at the dominant radius was associated to a marked increase in bone size and a slight improvement in volumetric bone mineral density, thereby improving bone strength. In addition to the muscle contractions, other mechanical stimuli seemed to exert a direct effect on bone tissue, contributing to the specific bone response to tennis playing.

Fleg JL, Morrell CH, Bos AG, et al. Accelerated longitudinal decline of aerobic capacity in healthy older adults. Circulation 2005; 112: 674–682.
The ability of older persons to function independently is dependent largely on the maintenance of sufficient aerobic capacity and strength to perform daily activities. Although peak aerobic capacity is widely recognized to decline with age, its rate of decline has been estimated primarily from cross-sectional studies that may provide misleading, overly optimistic estimates of aging changes. The longitudinal rate of decline in peak V̇o2 in healthy adults is not constant across the age span in healthy persons, as assumed by cross-sectional studies, but accelerates markedly with each successive age decade, especially in men, regardless of physical activity habits. The accelerated rate of decline of peak aerobic capacity has substantial implications with regard to functional independence and quality of life, not only in healthy older persons, but particularly when disease-related deficits are superimposed. 

Ichikawa T, Horie-Inoue K, Ikeda K, Blumberg B, Inoue S. Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells. J Biol Chem. 2006;281:16927–16934. 

Mithieux SM & Weiss AS.  Elastin. Adv Protein Chem. 2005;70:437–461.
Elastin is a key extracellular matrix protein that is critical to the elasticity and resilience of many vertebrate tissues including large arteries, lung, ligament, tendon, skin, and elastic cartilage. Elastin sequences interact with multiple proteins found in or colocalized with microfibrils, and bind to elastogenic cell surface receptors. Knowledge of the major stages in elastin assembly has facilitated the construction of in vitro models of elastogenesis, leading to the identification of precise molecular regions that are critical to elastin-based protein interactions.

Nishimoto SK & Nishimoto M.  Matrix Gla protein C‐terminal region binds to vitronectin. Co‐localization suggests binding occurs during tissue developmentMatrix Biology.  2005;24(5):353–361.
The current study demonstrates that MGP has a novel binding activity for vitronectin, an extracellular protein that promotes cell-matrix interactions and regulates coagulation.

Cockayne S, Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ. Vitamin K and the Prevention of Fractures. Arch Int Med. 2006;166:1256–1261.
This systematic review suggests that supplementation with phytonadione (a man made form of vitamin K) and menaquinone-4 reduces bone loss. In the case of the latter, there is a strong effect on incident fractures among Japanese patients. 

Hadjidakis DJ, Androulakis II.  Bone remodeling.  Ann N Y Acad Sci.  2006 Dec:1092:385-96.
The skeleton is a metabolically active organ that undergoes continuous remodeling throughout life. Bone remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix through the osteoblasts that subsequently become mineralized. The remodeling cycle consists of three consecutive phases: resorption, during which osteoclasts digest old bone; reversal, when mononuclear cells appear on the bone surface; and formation, when osteoblasts lay down new bone until the resorbed bone is completely replaced. Bone remodeling serves to adjust bone architecture to meet changing mechanical needs and it helps to repair microdamages in bone matrix preventing the accumulation of old bone. It also plays an important role in maintaining plasma calcium homeostasis. The regulation of bone remodeling is both systemic and local. The major systemic regulators include parathyroid hormone (PTH), calcitriol, and other hormones such as growth hormone, glucocorticoids, thyroid hormones, and sex hormones. Furthermore, the processes of bone resorption and formation are tightly coupled allowing a wave of bone formation to follow each cycle of bone resorption, thus maintaining skeletal integrity. 

Heaney RP. Bone as the calcium nutrient reserve. In: Weaver CM, Heaney RP, Editors.  Calcium in Human Health. Nutrition and Health. Totowa, NJ: Humana Press; 2006. p. 7-12.

Karsenty, G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab. 2006;4:341–348. 

Neogi T, Booth SL, Zhang YQ, Jacques PF, Terkeltaub R, Aliabadi P, Felson DT. Low vitamin K status is associated with osteoarthritis in the hand and knee. Arthritis Rheum. 2006;54:1255–61.
Poor intake of vitamin K is common. Insufficient vitamin K can result in abnormal cartilage and bone mineralization. Furthermore, osteophyte growth, seen in osteoarthritis (OA), may be a vitamin K-dependent process. We undertook this study to determine whether vitamin K deficiency is associated with radiographic features of OA. We conducted an analysis among 672 participants (mean age 65.6 years, 358 women) in the Framingham Offspring Study, a population-based prospective observational cohort. Levels of plasma phylloquinone (the primary form of vitamin K) had previously been measured in these participants, for whom we also had bilateral hand and knee radiographs. These observational data support the hypothesis of an association between low plasma levels of vitamin K and increased prevalence of OA manifestations in the hand and knee.

Radad K, Rausch WD, Gille G. Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respirationNeurochem Int.  2006;49:379–86.
Although the definite etiology of Parkinson's disease is still unclear, increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in increasing the risk of developing Parkinson's disease. In the present study, primary cultures prepared from embryonic mouse mesencephala were applied to investigate the toxic effects and underlying mechanisms of rotenone-induced neuronal cell death relevant to Parkinson's disease. Results revealed that rotenone destroyed dopaminergic neurons in a dose- and time-dependent manner. Rotenone exerted toxicity by decreasing the mitochondrial membrane potential, increasing reactive oxygen species production and shifting respiration to a more anaerobic state.

Ruohola J-P, Laaksi I, Ylikomi T, Haataja R, Mattila VM, Sahi T, et al.  Association between serum 25(OH)D concentrations and bone stress fractures in Finnish young men.  J Bone Miner Res.  2006 Sep;21(9):1483-88.
Low vitamin D level may predict rickets, osteomalacia, or osteoporosis. We examined serum 25(OH)D concentration as a predisposing factor for bone stress fracture in 756 military recruits. Fatigue bone stress fracture is one of the most frequently seen types of overuse injuries in athletes and military recruits. An association was recently shown between vitamin D and BMC. A correlation has also been found between low femoral BMD and stress fractures. We measured serum 25(OH)D concentration in a population sample of military recruits to determine if vitamin D is a predisposing factor for fatigue bone stress fracture.The average serum 25(OH)D concentration was significantly lower in the group with fracture, suggesting a relationship between vitamin D and fatigue bone stress fracture.

Saltin B, Calbet JA. Point: in health and in a normoxic environment, Vo2max is limited primarily by cardiac output and locomotor muscle blood flow. J Appl Physiol2006;100:744–745.
In summary, in healthy humans, V̇o2 max at sea level is limited by systemic oxygen delivery and especially by O2 delivery to the locomotor muscles. Oxygen delivery, in turn, depends on the ability of the cardiorespiratory system (i.e., lungs, heart, and blood) to transport and distribute appropriately O2 to the active motor units, rather than on the mitochondrial oxidative capacity, which in human skeletal muscles exceeds widely maximal O2 supply in all known exercise models. 

Suominen H. Muscle training for bone strength. Aging Clin Exp Res 2006;18:85-93. Further research is needed on dose-response relationships between exercise and bone strength, the feasibility of high-load, high-speed and impact-type of physical training, and the risks and benefits of intensive exercise in elderly individuals. The main function of bone is to provide the mechanical integrity for locomotion and protection; accordingly, bone mass and architecture are adjusted to control the strains produced by mechanical load and muscular activity. Age-related patterns involve peak bone mass during growth, a plateau in adulthood, and bone loss during aging. The decline in bone mass and structural integrity results in increased risk of fractures, particularly in post-menopausal women. Athletes competing in strength and power events, such as weight-lifting and jumping, have superior bone mass and structure compared with their untrained counterparts in all age groups. 

Bolton-Smith C, McMurdo ME, Paterson CR, Mole PA, Harvey JM, Fento, ST, et al.   Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. J Bone Min Res. 2007;22:509–519.

Knapen M, Schurgers, Vermeer C. Vitamin K 2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007;18:963–972.
Vitamin K mediates the synthesis of proteins regulating bone metabolism. We have tested whether high vitamin K2 intake promotes bone mineral density and bone strength. Results showed that K2 improved BMC and femoral neck width, but not DXA-BMD. Hence high vitamin K2 intake may contribute to preventing postmenopausal bone loss.

Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al.  Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130:456–469. 
By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.

Nielsen AR, Mounier R, Plomgaard P, Mortensen OH, Penkowa M, Speerschneider T, et al.  Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J Physiol. 2007;584:305–312.

Adami, S, et al., Physical activity and bone turnover markers: a cross-sectional and a 417 longitudinal study. Calcified Tissue International.  2008;83(6):388-392. Strenuous physical activity in young individuals has an important effect on both bone mass and bone turnover but the effect of moderate physical activity in adults remains uncertain. In a large cohort (N = 530) of healthy premenopausal women, bone formation markers (osteocalcin and N-terminal propeptide of type 1 procollagen [P1NP]), were found to be significantly associated with the level of physical activity, and this association remained significant after adjusting the data by age and body mass index.  In conclusion, both the cross-sectional and the longitudinal parts of our study demonstrate that even minor changes in physical activity are associated with a clear effect on bone formation markers.

Cheung AM, Tile L, Lee Y, Tomlinson G, Hawker G, Scher J, et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): A randomized controlled trial. PLoS Med. 2008;5:e196.

Clifford PS, Tschakovsky ME.  Rapid vascular responses to muscle contraction.  Exercise & Sport Sci Revs.  2008 Jan;36(1):25-9.
Continuous measurements reveal that muscle blood flow increases within the first second after contraction. The increase in blood flow is attributable to rapid vasodilation as confirmed by direct observations of arterioles within contracting muscles. New evidence suggests that mechanical deformation of the vascular wall during contraction may be a causative factor.

Danziger J.  Vitamin K-dependent proteins, warfarin, and vascular calcification.  Clin J Am Soc Nephrol.  2008 Sep;3(5):1504-10.
Vitamin K-dependent proteins (VKDPs) require carboxylation to become biologically active. Although the coagulant factors are the most well-known VKDPs, there are many others with important physiologic roles. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs, and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature; MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Unlike the coagulant factors, which undergo hepatic carboxylation, MGP and Gas-6 are carboxylated within the vasculature. This peripheral carboxylation process is distinct from hepatic carboxylation, yet both are inhibited by warfarin administration. Warfarin prevents the activation of MGP and Gas-6, and in animals, induces vascular calcification. Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarin's effect on VKDPs is paramount. Furthermore, recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.

Duncker DJ, Bache RJ. Regulation of coronary blood flow during exercisePhysiol Rev. 2008;88:1009–86.
Exercise is the most important physiological stimulus for increased myocardial oxygen demand. The requirement of exercising muscle for increased blood flow necessitates an increase in cardiac output that results in increases in the three main determinants of myocardial oxygen demand: heart rate, myocardial contractility, and ventricular work. The approximately sixfold increase in oxygen demands of the left ventricle during heavy exercise is met principally by augmenting coronary blood flow (~5-fold), as hemoglobin concentration and oxygen extraction (which is already 70-80% at rest) increase only modestly in most species. In contrast, in the right ventricle, oxygen extraction is lower at rest and increases substantially during exercise, similar to skeletal muscle, suggesting fundamental differences in blood flow regulation between these two cardiac chambers. The increase in heart rate also increases the relative time spent in systole, thereby increasing the net extravascular compressive forces acting on the microvasculature within the wall of the left ventricle, in particular in its subendocardial layers. Hence, appropriate adjustment of coronary vascular resistance is critical for the cardiac response to exercise. Exercise training does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced.

Duscha BD, Schulze PC, Robbins JL, Forman DE. Implications of chronic heart failure on peripheral vasculature and skeletal muscle before and after exercise trainingHeart Fail Rev.  2008;13:21–37.
The pathophysiology of chronic heart failure (CHF) is typically conceptualized in terms of cardiac dysfunction. However, alterations in peripheral blood flow and intrinsic skeletal muscle properties are also now recognized as mechanisms for exercise intolerance that can be modified by therapeutic exercise. This overview focuses on blood delivery, oxygen extraction and utilization that result from heart failure. Related features of inflammation, changes in skeletal muscle signaling pathways, and vulnerability to skeletal muscle atrophy are discussed. Specific focus is given to the ways in which perfusion and skeletal muscle properties affect exercise intolerance and how peripheral improvements following exercise training increase aerobic capacity. We also identify gaps in the literature that may constitute priorities for further investigation.

Haugen T, Paulsen G, Seiler S, Sandbakk O. New records in human powerInt J Sports Physiol Perform. 2008;13:678–686.  
Maximal aerobic and anaerobic power are crucial performance determinants in most sport disciplines. Numerous studies have published power data from elite athletes over the years, particularly in runners, cyclists, rowers, and cross-country (XC) skiers. This invited review defines the current "world records" in human upper limits of aerobic and anaerobic power. Currently, max values of ∼7.5 and 7.0 L·min-1 in male XC skiers and rowers, respectively, and/or ∼90 mL·kg-1·min-1 in XC skiers, cyclists, and runners can be described as upper human limits for aerobic power. Corresponding values for women are slightly below 5.0 L·min-1 in rowers and XC skiers and ∼80 mL·kg-1·min-1 in XC skiers and runners. Extremely powerful male athletes may reach ∼85 W·kg-1 in countermovement jump (peak vertical power) and ∼36 W·kg-1 in sprint running (peak horizontal power), cycling (instantaneous power during force-velocity testing from a standing position), and rowing (instantaneous power). Similarly, their female counterparts may reach ∼70 W·kg-1 in countermovement jump and ∼30 W·kg-1 in sprint running, cycling, and rowing. The presented values can serve as reference values for practitioners and scientists working with elite athletes. Doping is also a potential confounding factor when interpreting the human upper limits of aerobic and anaerobic power.

Lalande S, Gusso S, Hofman PL, Baldi JC.  Reduced leg blood flow during submaximal exercise in type 2 diabetes.  Med Sci Sports Exerc.  2008 Apr;40(4):612-7.
It is unclear whether impaired cardiac and/or vascular function contribute to exercise intolerance in patients with type 2 diabetes.  Magnetic resonance imaging (MRI) was used to determine whether reductions in cardiac output and/or femoral arterial blood flow contribute to reduced aerobic capacity in patients with type 2 diabetes.Cardiac and femoral arterial blood flow MRI scans were performed at rest and during low-intensity leg exercise in eight patients with type 2 diabetes and 11 healthy individuals. Maximal aerobic capacity VO(2 max) and maximal oxygen pulse were also determined in all participants. VO(2 max) was 20% lower and maximal oxygen pulse was 16% lower in patients with type 2 diabetes (P < 0.05), whereas maximal heart rate was the same between groups. Low-intensity exercise induced a 20% increase in heart rate and cardiac output as well as a 60-70% increase in femoral blood flow in both groups (P < 0.05). Femoral arterial blood flow indexed to thigh lean mass was reduced during exercise in patients with type 2 diabetes compared with healthy individuals. Stroke volume indexed to fat-free mass was lower in patients with type 2 diabetes, but greater heart rate allowed cardiac output to be maintained during submaximal exercise.  These findings suggest that impaired femoral arterial blood flow, an indirect marker of muscle perfusion, affects low-intensity exercise performance in patients with type 2 diabetes. However, because of lower exercising stroke volume, we propose that femoral arterial blood flow and, possibly, cardiac output, limit V O(2 max) in patients with type 2 diabetes.

Levine BD. VO2max: what do we know, and what do we still need to know? J Physio. 2008;586:25–34.
Maximal oxygen uptake (.VO(2,max)) is a physiological characteristic bounded by the parametric limits of the Fick equation: (left ventricular (LV) end-diastolic volume--LV end-systolic volume) x heart rate x arterio-venous oxygen difference. 'Classical' views of VO(2,max) emphasize its critical dependence on convective oxygen transport to working skeletal muscle, and recent data are dispositive, proving convincingly that such limits must and do exist. Elite endurance athletes have a high VO(2,max) due primarily to a high cardiac output from a large compliant cardiac chamber (including the myocardium and pericardium) which relaxes quickly and fills to a large end-diastolic volume. This large capacity for LV filling and ejection allows preservation of blood pressure during extraordinary rates of muscle blood flow and oxygen transport which support high rates of sustained oxidative metabolism. The magnitude and mechanisms of cardiac phenotype plasticity remain uncertain and probably involve underlying genetic factors, as well as the length, duration, type, intensity and age of initiation of the training stimulus.

Pedersen BK, Febbraio MA. Muscle as an endocrine organ: Focus on muscle-derived interleukin-6.  Physiol Rev.  2008;88:1379–1406.
Skeletal muscle has recently been identified as an endocrine organ. It has, therefore, been suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert paracrine, autocrine, or endocrine effects should be classified as "myokines." However, the first identified and most studied myokine is the gp130 receptor cytokine interleukin-6 (IL-6). This review focuses on the myokine IL-6, its regulation by exercise, its signaling pathways in skeletal muscle, and its role in metabolism in both health and disease.

Shearer MJ, Newman P.  Metabolism and cell biology of vitamin K.  Thromb Haemost.  2008 Oct;100(4):530-47.
Naturally occurring vitamin K compounds comprise a plant form, phylloquinone (vitamin K(1)) and a series of bacterial menaquinones (MKs) (vitamin K(2)). Structural differences in the isoprenoid side chain govern many facets of metabolism of K vitamins including the way they are transported, taken up by target tissues, and subsequently excreted. In the post-prandial state, phylloquinone is transported mainly by triglyceride-rich lipoproteins (TRL) and long-chain MKs mainly by low-density lipoproteins (LDL). TRL-borne phylloquinone uptake by osteoblasts is an apoE-mediated process with the LRP1 receptor playing a predominant role. One K(2) form, MK-4, has a highly specific tissue distribution suggestive of local synthesis from phylloquinone in which menadione is an intermediate. Both phylloquinone and MKs activate the steroid and xenobiotic receptor (SXR) that initiates their catabolism, but MK-4 specifically upregulates two genes suggesting a novel MK-4 signalling pathway. Many studies have shown specific clinical benefits of MK-4 at pharmacological doses for osteoporosis and cancer although the mechanism(s) are poorly understood. Other putative non-cofactor functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and thereby the availability of reduced vitamin K. In humans, MK-7 has a greater efficacy than phylloquinone in carboxylating both liver and bone Gla proteins. A daily supplement of phylloquinone has shown potential for improving anticoagulation control.

Tsugawa N, Shiraki M, Suhara Y, Kamao M, Ozaki R, Tanaka K, et al.  Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women. J Bone Min Metab. 2008;26:79–85. 
The objectives were to evaluate the association between plasma phylloquinone (K1) or menaquinone (MK-4 and MK-7) concentration and BMD or fracture in Japanese women prospectively. A total of 379 healthy women aged 30-88 years (mean age, 63.0 years) were consecutively enrolled.  When subjects were divided into low and high K1 groups by plasma K1 concentration, the incidence of vertebral fracture in the low K1 group (14.4%) was significantly higher than that in the high K1 group (4.2%), and its age-adjusted RR was 3.58 (95% CI, 3.26-3.93). L2-4 BMD was not different between the two groups. These results suggest that subjects with vitamin K1 insufficiency in bone have increased susceptibility for vertebral fracture independently from BMD.

Weibel ER, Hoppeler H. 
Exercise-induced maximal metabolic rate scales with muscle aerobic capacityJ Exp Biol. 2008:1635–1644.
The researchers conclude that the scaling of maximal metabolic rate is determined by the energy needs of the cells active during maximal work. The vascular supply network is adapted to the needs of the cells at their working limit. We conjecture that the optimization of the arterial tree by fractal design is the result rather than the cause of the evolution of metabolic rate scaling. The remaining question is why the energy needs of locomotion scale with the 0.872 or 7/8 power of body mass.

Wilkinson SB, Phillips SM, Atherton PJ, Patel R, Yarasheski KE, Tarnopolsky MA, et al.  Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle.  J Physiol.  2008 Aug 1; 586(15):3701-17. 

Yaegashi Y, Onoda T, Tanno K, Kuribayashi T, Sakata K, Orimo, H. Association of hip fracture incidence and intake of calcium, magnesium, vitamin D, and vitamin K. Eur. J. Epidemiol. 2008;23:219–225.
To analyze the association between hip fracture incidence in 12 regional blocks within Japan and dietary intake of four key nutrients: calcium, magnesium, vitamin D, and vitamin K.  An ecological study. Using data from the 2002 national survey on the incidence of hip fracture and the National Nutritional Survey of Japan, a standardized incidence ratio of hip fracture was calculated, and the association between the standardized incidence ratio and each nutritional intake was assessed for each region The significant correlation between hip fracture incidence and vitamin K intake, and also regional variations in food patterns, suggest that increasing intake of vegetables and legumes might lead to a decrease in hip fracture incidence in the future. Further, this study suggests that a review of the dietary reference value of vitamin K from the perspective of osteoporosis would be useful. 

Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, et al.  High dietary menaquinone intake is associated with reduced coronary calcificationAtherosclerosis. 2009;203(2):489–493.
Dietary vitamin K is thought to decrease risk of cardiovascular disease by reducing coronary calcification, but inconsistent results are reported. This may be due to different effects of vitamin K(1) (phylloquinone) and vitamin K(2) (menaquinone, MK), but few studies included both. We investigated the association of intake of phylloquinone and menaquinone, including its subtypes (MK4-MK10), with coronary calcification in a cross-sectional study among 564 post-menopausal women. Phylloquinone and menaquinone intake was estimated using a food-frequency questionnaire.  Phylloquinone intake was not associated with coronary calcification with a relative risk. Menaquinone intake was associated with decreased coronary calcification with an RR of 0.80 (95%-CI: 0.65-0.98; p(trend)=0.03).  This study shows that high dietary menaquinone intake, but probably not phylloquinone, is associated with reduced coronary calcification. Adequate menaquinone intakes could therefore be important to prevent cardiovascular disease.

Binkley N, Harke J, Krueger D, Engelke J, Vallarta-Ast N, Gemar D, et al.  Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women. J Bone Min Res. 2009;24:983–991.

Fuerst M, Bertrand J, Lammers L, Dreier R, Echtermeyer F, Nitschke Y, et al. Calcification of articular cartilage in human osteoarthritis. Arthritis Rheum. 2009;60:2694–703.  

Gast GCM, De Roos NM, Sluijs I, Bots ML,  Beulens JWJ, Geleijnse JM, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009;19;504–510.
Vitamin K dependent proteins have been demonstrated to inhibit vascular calcification. Data on the effect of vitamin K intake on coronary heart disease (CHD) risk, however, are scarce. Using data from the Prospect-EPIC cohort, the researchers examined the relationship between dietary vitamins K(1) and K(2) intake, and its subtypes, and the incidence of CHD.  They found that a high intake of menoquinones, especially MK-7, MK-8 and MK-9, could protect against CHD. However, more research is necessary to define optimal intake levels of vitamin K intake for the prevention of CHD.

Iwamoto J, Sato Y, Takeda T, Matsumoto H.  High-dose vitamin K supplementation reduces fracture incidence in postmenopausal women: a review of the literature.  Nutr Res. 2009 Apr;29(4):221-228.
Although systematic review and meta-analysis of randomized controlled trials (RCTs) have concluded that vitamin K is effective in preventing fractures, the effect of vitamin K on the skeleton remains a matter of controversy. The objective of the present review of the literature was to evaluate the effect of vitamin K supplementation on the skeleton of postmenopausal women. PubMed was used to search the reliable literature for RCTs by using the search terms "vitamin K(1) or vitamin K(2)," "bone," and "postmenopausal women" and the following inclusion criteria: approximately 50 or more subjects per group and study period of 2 years or longer. Seven RCTs met the inclusion criteria. The results of these RCTs showed that vitamin K(1) and vitamin K(2) supplementation reduced serum undercarboxylated osteocalcin levels regardless of dose but that it had inconsistent effects on serum total osteocalcin levels and no effect on bone resorption. Despite the lack of a significant change or the occurrence of only a modest increase in bone mineral density, high-dose vitamin K(1) and vitamin K(2) supplementation improved indices of bone strength in the femoral neck and reduced the incidence of clinical fractures. 

McGavock JM, Hastings JL, Snell PG, et al. A forty-year follow-up of the Dallas Bed Rest and Training study: the effect of age on the cardiovascular response to exercise in men. J Gerontol A Biol Sci Med Sci 2009;64:293–299. 
In 1966, five 20-year-old men underwent a comprehensive physiological evaluation of the capacity for adaptation of the cardiovascular system in response to 3 weeks of bed rest and 8 weeks of heavy endurance training; these same participants were reevaluated before and after training at the age of 50. The aim of the present study was to reexamine these same men 40 years following the original assessments. In the original five participants of the Dallas Bed Rest and Training Study, VO(2max) declined after 40 years of living due to a balanced decrease in central and peripheral determinants of oxygen uptake. The rate of decline in VO(2max) and its components accelerated after the age of 50 years secondary to age and clinical comorbidities. The net proportional decline in VO(2max) for a period of 40 years of life was comparable with that experienced after 3 weeks of strict bed rest at the age of 20 (27% vs 26%, respectively). 

Ng KW, Martin TJ. New functions for old hormones: Bone as an endocrine organ. Mol Cell Endocrinol. 2009;310:1–2.

Nilsson M, Ohlsson C, Mellstroem D, Lorentzon M. Previous sport activity during childhood and adolescence is associated with increased cortical bone size in young adult men. J Bone Miner Res2009;24:125–33. 
Physical activity during growth has been associated with altered cortical bone geometry, but it remains uncertain if the physical activity-induced increments in cortical bone size remain when the level of physical activity is diminished or ceased. The aim of this study was to investigate if physical activity during growth is associated with cortical bone geometry in currently inactive young men. In this study, 1068 men (18.9 +/- 0.6 [SD] yr) were included. Subjects who continued to be active (n = 678) and who had been previously active (n = 285) in sports had a wider cortical bone (periosteal circumference [PC], 4.5% and 3.2%, respectively) with increased cross-sectional area (CSA; 12.5% and 6.9%) of the tibia than the always inactive subjects (n = 82). Amount of previous sport activity explained 7.3% of the total variation in cortical cross sectional area. Subjects, who ceased their sport activity for up to 6.5 yr previously, still had greater cortical PC and CSA of the tibia than always inactive subjects. The results from this study indicate that sport activity during growth confers positive effects on bone geometry even though sport activity is ceased.

Robling AG, Turner CH.  Mechanical signaling for bone modeling and remodeling.  Crit Rev Eukaroy Gene Expr. 2009;19(4):319-38.
Proper development of the skeleton in utero and during growth requires mechanical stimulation. Loading results in adaptive changes in bone that strengthen bone structure. Bone's adaptive response is regulated by the ability of resident bone cells to perceive and translate mechanical energy into a cascade of structural and biochemical changes within the cells a process known as mechanotransduction. Mechanotransduction pathways are among the most anabolic in bone, and consequently, there is great interest in elucidating how mechanical loading produces its observed effects, including increased bone formation, reduced bone loss, changes in bone cell differentiation and lifespan, among others. A molecular understanding of these processes is developing, and with it comes a profound new insight into the biology of bone. In this article, we review the nature of the physical stimulus to which bone cells mount an adaptive response, including the identity of the sensor cells, their attributes and physical environment, and putative mechanoreceptors they express. The cellular mechanisms for increased bone loss during disuse, and reduced bone loss during loading are considered. Finally, we summarize the published data on bone cell accommodation, whereby bone cells stop responding to mechanical signaling events. Collectively, these data highlight the complex yet finely orchestrated process of mechanically regulated bone homeostasis.

Russo CR. The effects of exercise on bone. Basic concepts and implications for the prevention of fractures. Clin Cases Miner Bone Metab2009;6:223–8. 

Osteogenic dynamic loads delivered to the skeleton during exercise prevent aging-associated bone fragility. Moreover, because of its favorable effects on health, exercise improves quality of life, and specific types of exercise increase muscle strength, a known predictor of bone strength, and coordination and balance, and so reduce the risk of fall related fractures. Exercise should definitely be the mainstay of the prevention and treatment of osteoporosis; often however, physicians don’t have enough know-how for evidence based prescription of exercise. Moreover, the lack of facilities for safe implementation of the exercise programs compound the problem. Scientific societies and health authorities should invest in patient and physicians education about exercise and in promoting facilities (Gyms) devoted to training of persons with, or at risk of, metabolic diseases (osteoporosis, obesity, diabetes), like Metagym in Florence, Italy. 

Shea MK, O’Donnell CJ,  Hoffmann U, Dallal GE, Dawson-Hughes B,  Ordovas J, et al.   Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am. J Clin Nutr 2009;89:1799–1807.
The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control).  In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). They concluded that phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. 

Zechner R, Kienesberger PC, Haemmerle G, Zimmermann R, Lass A. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J Lipid Res. 2009;50(1):3–21. 

2010s

Banfi G, Lombardi G, Colombini A, Lippi  G.  Bone metabolism markers in sports medicine.  Sports Med.  2010 Aug 1;40(8):697-714.
Bone mass can be viewed as the net product of two counteracting metabolic processes, bone formation and bone resorption, which allow the skeleton to carry out its principal functions: mechanical support of the body, calcium dynamic deposition and haemopoiesis. Physical exercise is a known source of bone turnover and is recommended for preventing osteoporosis and bone metabolism problems.  Few studies on bone metabolism markers have evaluated their performance in elite and top-level athletes, who have a higher bone turnover than sedentary individuals. Despite discrepant results among studies, most have shown that short exercise is insufficient for modifying serum concentrations of bone metabolism markers. Marker variations are more evident after several hours or days after exercise, bone formation markers are more sensitive than bone resorption markers, and stimulation of osteoblast and/or osteoclast functions is exercise dependent but the response is not immediate. The response depends on the type of exercise; the markers seem to be less sensitive to resistance exercise and the intensity of exercise is not discriminate. Comparisons between trained subjects and untrained controls have demonstrated the influence of exercise on bone turnover. After prolonged training and competition, bone formation markers are found to change in sedentary subjects enrolled in a physical activity programme. Professional athletes show changes in bone formation markers depending on programme intensity, whereas bone resorption appears to stabilize. Crucial for long-term training, are the characteristics of exercise (e.g. weight-bearing, impact). 

Da Poian AT, El-Bacha T, Luz RMP.  Nutrient utilization in humans:  metabolism pathways.  Nature Education.  2010;3(9):11.
Where does the energy that makes life possible come from? Humans obtain energy from three classes of fuel molecules: carbohydrates, lipids, and proteins. The potential chemical energy of these molecules is transformed into other forms, such as thermal, kinetic, and other chemical forms.

Ding WX,  Ni H-M, Li M, Liao Y, Chen X, Stolz DB, et al. Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J Biol Chem. 2010a;285(36):27879–27890.

Emaus N, Gjesdal CG, Almås B, Christensen M, Grimsgaard A, Berntsen G, et al.  Vitamin K2 supplementation does not influence bone loss in early menopausal women: A randomised double-blind placebo-controlled trial. Osteoporos Int. 2010;21:1731–1740. 

Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePiknho RA, Teti A, Ducy P, et al.  Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism.  Cell.  2010 Jul 23;142(2):296-308.
A cell type expressing this receptor is the osteoblast, a bone-specific cell favoring glucose metabolism through a hormone, osteocalcin, that becomes active once uncarboxylated. We show here that insulin signaling in osteoblasts is necessary for whole-body glucose homeostasis because it increases osteocalcin activity. To achieve this function insulin signaling in osteoblasts takes advantage of the regulation of osteoclastic bone resorption exerted by osteoblasts. Indeed, since bone resorption occurs at a pH acidic enough to decarboxylate proteins, osteoclasts determine the carboxylation status and function of osteocalcin. Accordingly, increasing or decreasing insulin signaling in osteoblasts promotes or hampers glucose metabolism in a bone resorption-dependent manner in mice and humans. Hence, in a feed-forward loop, insulin signals in osteoblasts activate a hormone, osteocalcin, that promotes glucose metabolism. 

Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, Faugere M-C, Aja S, et al.  Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition.  Cell.  2010 Jul 23;142(2):309-19.
Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition and is a potent insulin secretagogue. Here, we show that insulin receptor (IR) signaling in osteoblasts controls osteoblast development and osteocalcin expression by suppressing the Runx2 inhibitor Twist2. Mice lacking IR in osteoblasts have low circulating undercarboxylated osteocalcin and reduced bone acquisition due to decreased bone formation and deficient numbers of osteoblasts. The metabolic abnormalities in these mice are improved by infusion of undercarboxylated osteocalcin. These results indicate the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast ensures osteoblast differentiation and stimulates osteocalcin production, which in turn regulates insulin sensitivity and pancreatic insulin secretion. 

Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 2010;12(2):119–131.

Geng T, Li P, Okutsu M, Yin X, Kwek J, Zhang M, Yan Z. 2010. PGC-1α plays a functional role in exercise-induced mitochondrial biogenesis and angiogenesis but not fiber-type transformation in mouse skeletal muscleAm J Physiol Cell Physiol. 2010; 298(3): C572–C579. 
Endurance exercise stimulates peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) expression in skeletal muscle, and forced expression of PGC-1alpha changes muscle metabolism and exercise capacity in mice. We conclude that PGC-1alpha is required for complete skeletal muscle adaptations induced by endurance exercise in mice.

Iwamoto J, Takeda T, Uenishi K, Ishida H, Sato Y, Massumoto H.  Urinary levels of cross-linked N-terminal telopeptide of type 1 collagen and nutritional status in Japanese professional baseball players.  J Bone Miner Metab.  2010;28(5):540-46. 

Jakobsen LH, Rask IK, Kondrup J, et al.  Validation of handgrip strength and endurance as a measure of physical function and quality of life in healthy subjects and patients.  Nutrition.  2010;26:542-550. 

Machado-Fragua MD, Hoogendijk EO, Struijk EA, Rodriguez-Artalejo F, Lopez-Garcia E, Beulens JW, et al.  High despho-uncarboxylated matrix Gla protein concentrations, a plasma biomarker of vitamin K, in relation to frailty:  the Longitudinal Aging Study Amsterdam.  E J Nutr.  2010;59:1243-1251.
No previous study has evaluated the relationship between vitamin K and frailty. Thus, we assessed the relationship between vitamin K status and frailty over 13 years in the Longitudinal Aging Study Amsterdam (LASA). Methods Prospective cohort study with 644 community-dwelling adults ≥ 55 years from the LASA cohort. Frailty was measured at baseline and in four follow-up examinations with the LASA Frailty Index (LASA-FI), which was used as both a continuous and a dichotomous measure (FI ≥ 0.25), as indicator of the degree of frailty and frailty risk, respectively. Baseline plasma low vitamin K status was associated with a greater degree of frailty and frailty risk in this cohort of older adults, which highlights the importance of ensuring an optimal nutritional status of this vitamin to prevent frailty in later life. 

Mehta DS, Vaidya RA, Doung YA, Nabar NS, Pandey SN,, Vaidya ADB.  Therapeutic activity and safety of vitamin K2-7 in muscle cramps:  an interventional case-series.  The Indian Practitioner.  2010 May;63(5):287-91.
To study the safety, tolerability and therapeutic activity of MK7 in a series of patients with idiopathic muscle cramps – systremma. 19 patients presenting with muscle cramps.  100ug/capsul day of MK7 given orally for 3 months. Blood  biochemistry and organ function tests were studied at baseline and at the end of therapy for safety.  Group A had 102 cramps per day with severity of 2-0.  Group B had 204/ week at least once a week.  Results showed that patients from both groups experienced a reduction in the frequency.  Duration and intensity of cramps was also reduced in Group B. Vitamin K 2-7 at a dose of 100 µg /day for 3 months was found to be well tolerated and safe with a therapeutic relief of muscle cramps.  

Ohsaki Y, Shirakawa H, Miura A, Giriwono PE, Sato S, Ohashi A, et al.  Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor κB  through the repression of IKKα/β phosphorylation.  J Nutr Biochem.  2010;21:1120-1126. 
Vitamin K is essential for blood coagulation and bone metabolism in mammals. This vitamin functions as a cofactor in the posttranslational synthesis of γ-carboxyglutamic acid (Gla) from glutamic acid residues. However, other functions of vitamin K have been reported recently. We previously found that vitamin K suppresses the inflammatory reaction induced by lipopolysaccharide (LPS) in rats and human macrophage-like THP-1 cells. In this study, we further investigated the mechanism underlying the anti-inflammatory effect of vitamin K by using cultures of LPS-treated human- and mouse-derived cells. All the vitamin K analogues analyzed in our study exhibited varied levels of anti-inflammatory activity. The results of our study suggest that the 2-methyl-1,4-naphtoquinone ring structure contributes to express the anti-inflammatory activity, which is independent of the Gla formation activity of vitamin K. Furthermore, menaquinone-4, reduced the activation of nuclear factor κB (NFκB) and inhibited the phosphorylation of IKKα/β after treatment of cells with LPS. These results clearly show that the anti-inflammatory activity of vitamin K is mediated via the inactivation of the NFκB signaling pathway. 

Perry CG, Lally J, Holloway GP, Heigenhauser GJ, Bonen A, Spriet LL. 2010. Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscleJ Physiol. 2010;588:4795–4810.  

Rennenberg RJ, de Leeuw PW, Kessels AG et al. Calcium scores and matrix Gla protein levels: association with vitamin K statusEur J Clin Invest. 2010;40:344–9.
Vascular calcification in humans is associated with an increased cardiovascular risk. Carboxylated matrix Gla protein (cMGP) inhibits vascular calcification. Vitamin K is an essential cofactor for the activation of uncarboxylated matrix Gla protein (ucMGP). It has been suggested that patients on long-term treatment with vitamin K antagonists develop aortic valve calcifications because of lower levels of circulating MGP. We therefore hypothesized that arterial calcification and a low vitamin K status are associated with ucMGP. To that aim, we measured arterial calcium scores, the osteocalcin ratio (OCR), as a proxy for vitamin K status, and ucMGP. We found a positive association of total arterial calcium score and a high OCR (reflecting low vitamin K status) with ucMGP serum levels. This warrants further studies to explore the pathophysiological background of this phenomenon. 

Schurgers LJ, Barreto DV, Barreto FC, Liabeuf S, Renard C, Magdeleyns, E, et al.  The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: A preliminary report. Clin J Am Soc Nephrol. 2010;5:568–575.
Vitamin K-dependent matrix Gla protein (MGP) acts as a calcification inhibitor in vitro and in vivo. The present study was performed to (1) determine plasma levels of the inactive, dephosphorylated, uncarboxylated MGP (dp-ucMGP) in a cohort of patients at different stages of chronic kidney disease (CKD) and (2) evaluate the association between dp-ucMGP levels on one hand and aortic calcification and mortality on the other. Plasma dp-ucMGP levels augmented progressively with CKD stage, with a significant difference from CKD stage 4. CKD stage, hemoglobin, age, and coumarin use were independently associated with plasma dp-ucMGP levels. Furthermore, plasma dp-ucMGP and age were positively and independently associated with the aortic calcification score. They concluded that plasma dp-ucMGP increased progressively in a CKD setting and was associated with the severity of aortic calcification. Plasma dp-ucMGP could thus be a surrogate marker for vascular calcification in CKD.

Shiraki M, Shiraki Y, Aoki C, Miura M. Vitamin K2 (Menatetrenone) Effectively Prevents Fractures and Sustains Lumbar Bone Mineral Density in Osteoporosis. J Bone Miner Res. 2010;15:515–521.
We attempted to investigate whether vitamin K2 (menatetrenone) treatment effectively prevents the incidence of new fractures in osteoporosis. A total of 241 osteoporotic patients were enrolled in a 24-month randomized open label study. The control group (without treatment; n = 121) and the vitamin K2-treated group (n = 120), which received 45 mg/day orally vitamin K2, were followed for lumbar bone mineral density (LBMD; measured by dual-energy X-ray absorptiometry [DXA]) and occurrence of new clinical fractures. These findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures, although the vitamin K2-treated group failed to increase in LBMD. Furthermore, vitamin K2 treatment enhances gamma-carboxylation of the OC molecule.

Sun Y, Mauerhan DR, Honeycutt PR, Kneisl JS, Norton HJ, Zinchenko N, et al.  Calcium deposition in osteoarthritic meniscus and meniscal cell culture. Arthritis Res Ther. 2010;12:R56.
Calcium crystals exist in the knee joint fluid of up to 65% of osteoarthritis (OA) patients and the presence of these calcium crystals correlates with the radiographic evidence of hyaline cartilaginous degeneration. This study sought to examine calcium deposition in OA meniscus and to investigate OA meniscal cell-mediated calcium deposition. OA meniscal cells calcify more readily than normal meniscal cells. Pathological meniscal calcification, which may alter the biomechanical properties of the knee meniscus, is potentially an important contributory factor to OA. 

Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg, G, et al.  Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Int Med. 2010;268:483–492.
Matrix Gla protein (MGP) is a calcification inhibitor and alterations in circulating MGP have been observed in different populations characterized by vascular calcification. They examined plasma levels of nonphosphorylated carboxylated and undercarboxylated MGP (dp-cMGP and dp-ucMGP, respectively) in 147 patients with symptomatic severe aortic stenosis and in matched healthy controls, and concluded that a dysregulated MGP system may have a role in the development of left ventricular dysfunction in patients with symptomatic AS. 

Wallin R, Schurgers LJ, Loeser RF. Biosynthesis of the vitamin K-dependent matrix Gla protein (MGP) in chondrocytes: a fetuin-MGP protein complex is assembled in vesicles shed from normal but not from osteoarthritic chondrocytes. Osteoarthritis Cartilage2010;18:1096–103. 
Mineralization has been observed in osteoarthritic cartilage but the mechanisms are incompletely understood. Vitamin K is an essential cofactor in post-translational modification of proteins where specific Glu residues become modified to Ca(++) binding gamma-carboxyglutamic acid residues (Gla). One such protein, matrix Gla protein (MGP), is a known mineralization inhibitor. This study determined if synthesis of MGP and formation of a fetuin-MGP protein complex was altered in chondrocytes and vesicles from osteoarthritis (OA) cartilage.  They found that the absence of cMGP and of the cMGP-fetuin complex in OA cells and OA vesicles may be an important mechanism for increased mineralization of osteoarthritic cartilage. 

Watt M, Spriet LL. Triacylglycerol lipases and metabolic control: implications for health and disease. Am J of Physol Endocrinol Metab. 2010;299(2):162–8

Chatrou ML, Reutelingsperger CP, Schurgers LJ. Role of vitamin K-dependent proteins in the arterial vessel wallHamostaseologie. 2011;31:251–257.
For many years the role of vitamin K was solely ascribed to coagulation and coagulation was thought to be involved only at the venous blood side. This view has dramatically changed with the discovery of vitamin K-dependent proteins outside the coagulation cascade and the role of coagulation factors at the arterial side. Vitamin K-dependent proteins are involved in the regulation of vascular smooth muscle cell migration, apoptosis, and calcification. Vascular calcification has become an important independent predictor of cardiovascular disease. Vitamin K-antagonists induce inactivity of inhibitors of vascular calcification, leading to accelerated calcification. The involvement of vitamin K-dependent proteins such as MGP in vascular calcification make that calcification is amendable for intervention with high intake of vitamin K.  

Ducy P. The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism.  Diabetologia.  2011;54:1291-1297.
Bone remodelling, which maintains bone mass constant during adulthood, is an energy-demanding process. They hypothesized that bone cells regulate energy metabolism through an endocrine mechanism. Studies to test this hypothesis identified osteocalcin, a hormone secreted by osteoblasts, as a positive regulator of insulin secretion, insulin resistance and energy expenditure. Remarkably, insulin signalling in osteoblasts is a positive regulator of osteocalcin production and activation via its ability to indirectly enhance bone resorption by osteoclasts. Hence, osteocalcin is part of a complex signalling network between bone and the organs. This review summarises the molecular and cellular bases of the present knowledge on osteocalcin biology and discusses the potential relevance of osteocalcin to human metabolism and pathology. 

Je SH, Joo N.-S, Choi B.-H, Kim K-M, Kim B-T, Park S.-B, et al.  Vitamin K supplement along with vitamin D and calcium eeduced serum concentration of undercarboxylated osteocalcin while increasing bone mineral density in Korean postmenopausal women over sixty-years-old. J Korean Med Sci. 2011;26:1093–1098. 

Nakano T, Tsugawa N, Kuwabara A, Kamao M, Tanaka K, Okano T.  High prevalence of hypovitaminosis D and K in patients with hip fracture.  Asia Pac J Clin Nutr.  2011;20(1):56-61.
Although hip fracture is considered to be associated with hypovitaminosis D and K, few reports have previously studied both of them. We have studied the vitamin D- and K-status as well as the general nutritional status in ninety-nine patients with hip fracture. Mean serum concentration of 25hydroxy-vitamin D (25OH-D) in female fractured patients was only approximately 9 ng/mL, suggesting severe vitamin D deficiency. There was no significant difference between the two groups in serum concentration of intact parathyroid hormone in both genders and serum 25OH-D levels in the male subjects. Plasma concentrations of phylloquinone (vitamin K1; PK) and menaquinone-7 (MK-7) were significantly lower in the fractured group than in the control group in both genders. In conclusion, our study has shown that patients with hip fracture have vitamin D and K deficiency independent of general malnutrition. 

Rämson R,  Jürimäe J,  Jürimäe T, Mäestu J.  The effect of 4-week training period on plasma neuropeptide Y, leptin and ghrelin responses in male rowers.  Eur J App Physio.  2012;112:1873-1880. 

Rantalainen T, Nikander R, Daly RM et al.  Exercise loading and cortical bone distribution at the tibial shaft.  Bone.  2011;48:786-791. 

Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, Griesmacher A, McClung M, et al.  Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment:  a need for international reference standards.  Osteoporos Int.  2011 Feb;22(2):391-420. 
Bone turnover markers (BTM), such as osteocalcin, predict fracture risk, and treatment-induced changes in specific markers account for a substantial proportion of fracture risk reduction. The aims of this report were to determine their clinical potential in the prediction of fracture risk and for monitoring the treatment of osteoporosis and to set an appropriate research agenda. Evidence from prospective studies was gathered through literature review of the PUBMED database between the years 2000 and 2010 and the systematic review of the Agency for Healthcare Research and Quality up to 2001. High levels of BTMs may predict fracture risk independently from bone mineral density in postmenopausal women. BTMs provide pharmacodynamic information on the response to osteoporosis treatment, and as a result, they are widely used for monitoring treatment in the individual.

Rachner TD, Khosla S, Hofbauer LC.  Osteoporosis; now and future.  Lancet.  2011;377:1276-1287.
Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets, including osteocalcin.

Safdar A, Bourgeois JM, Ogborn DI, Little JP, Hettinga BP, Akhtar M, et al.  Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci USA. 2011;108:4135–4140.
The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities.

Schlieper G,  Westenfeld R,  Krüger T, Cranenburg EC, Magdeleyns EJ,  Brandenburg VM, et al.   Circulating nonphosphorylated carboxylated matrix Gla protein predicts survival in ESRD. J Am Soc Nephrol. 2011;22:387–395.
The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K-dependent proteins associate with all-cause or cardiovascular mortality. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study. 

Ueland T, Dahl CP, Gullestad L, Aahkus S, Broch K, Skårdal R, Vermeer C, Aukrust P, et al.  Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure.  Clin Sci.  2011;121(3):119-27.
We recently demonstrated that circulating MGP [matrix Gla (γ-carboxylated glutamate) protein] levels were associated with left ventricular dysfunction and increased mortality in patients with symptomatic aortic stenosis. We hypothesized that patients with chronic HF (heart failure) would have dysregulated MGP levels. We examined plasma dp-cMGP (non-phosphorylated carboxylated MGP) and dp-ucMGP (non-phosphorylated undercarboxylated MGP) in 179 patients with chronic HF and matched healthy controls as well as the relationship between MGP and cardiac.  We found markedly enhanced plasma dp-cMGP and, in particular, of dp-ucMGP in chronic HF with increasing levels with disease severity. Finally, dp-ucMGP was associated with long-term heart transplant-free survival (n=48) in univariate analysis. However, plasma dp-ucMGP was markedly higher in patients who died because of progression of heart failure and gave prognostic information also in multivariate analysis. In conclusion, a dysregulated MGP system could be involved in left ventricular dysfunction in patients with chronic HF. 

Yamaguchi M, & Weitzmann MN. Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF‐κB activationInt J of Molecular Med.  2011;27(1):3–14.
Several bone protective factors are reported to exhibit stimulatory activities on bone formation coupled with inhibitory effects on bone resorption; one such factor is vitamin K2. Vitamin K species [K1 (phylloquinone) and K2 (menaquinone)] have long been associated with bone protective activities and are receiving intense interest as nutritional supplements for the prevention or amelioration of bone disease in humans.  We now show that vitamin K2 action on osteoblast and osteoclast formation and activity is accomplished by down-regulating basal and cytokine-induced NF-κB activation, by increasing IκB mRNA, in a γ-carboxylation-independent manner. 

Yoshikawa Y, Kode A, Xu L, Mosialou I, Silva BC, Ferron M, et al.  Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism.  J Bone Miner Res.  2011 Sep;26(0):2012-15.
The skeleton has been shown recently to regulate glucose metabolism through an osteoblast-specific hormone, osteocalcin, which favors β-cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. An implication of this finding is that a decrease in osteoblast numbers would compromise glucose metabolism in an osteocalcin-dependent manner. To test this hypothesis, osteoblasts were inducibly ablated by cross-breeding transgenic mice. Ablation of osteoblasts in adult mice profoundly affected glucose metabolism. While administration of osteocalcin reversed (fully) the glucose intolerance and reinstated normal blood glucose and insulin levels, it only partially restored insulin sensitivity and did not affect the improved gonadal fat weight and energy expenditure in osteoblast-depleted mice. These observations suggest that in addition to osteocalcin, other osteoblast-derived hormones may contribute to the emerging function of the skeleton as a regulator of energy metabolism.

Booth SL.  Vitamin K:  food composition and dietary intakes.  Foot Nutr Res. 2012;56: 10.3402/fnr.v56i0.5505.
Vitamin K is present in the diet in the forms of phylloquinone and menaquinones. Phylloquinone, which is the major dietary source, is concentrated in leafy plants and is the vitamin K form best characterized in terms of food composition and dietary intakes. In contrast, menaquinones are the product of bacterial production or conversion from dietary phylloquinone. Food composition databases are limited for menaquinones and their presence in foods varies by region. Dietary intakes of all forms of vitamin K vary widely among age groups and population subgroups. Similarly, the utilization of vitamin K from different forms and food sources appear to vary, although our understanding of vitamin K is still rudimentary in light of new developments regarding the menaquinones. 

Bori Z, Zhao Z, Koltai E, Fatouros IG, Jamurtas AZ, Douroudos II, et al. The effects of aging, physical training, and a single bout of exercise on mitochondrial protein expression in human skeletal muscleExp Gerontol. 2012;47:417–424.
Aging results in a significant decline in aerobic capacity and impaired mitochondrial function. We have tested the effects of moderate physical activity on aerobic capacity and a single bout of exercise on the expression profile of mitochondrial biogenesis, and fusion and fission related genes in skeletal muscle of human subjects. Our data suggest that moderate levels of regular physical activity increases a larger number of mitochondrial biogenesis-related gene expressions in young individuals than in aged subjects. Mitochondrial fission is impaired by aging and could be one of the most sensitive markers of the age-associated decline in the adaptive response to physical activity. 

Dalmeijer GW, van der Schouw YT, Magdeleyns E, et al.  The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein.  Atherosclerosis.  2012;225-:397-402.
Investigated whether menaquinone-7 (MK-7) supplementation increases carboxylation of MGP, in a randomized, double-blind, placebo-controlled trial.  Sixty participants (40-65 y) were randomly allocated to supplementation of 180 μg/d, 360 μg/d of MK-7 or placebo during 12 weeks. They found that menaquinone supplementation dose-dependently decreases dp-ucMGP concentrations, but does not affect other MGP species. Dp-ucMGP may serve as a non-invasive marker of vitamin K status.

Gibala MJ, Little JP, Macdonald MJ, Hawley JA. Physiological adaptations to low-volume, high-intensity interval training in health and disease. J Physiol. 2012;590:1077–1084.
Exercise training is a clinically proven, cost-effective, primary intervention that delays may prevent the health burdens associated with many chronic diseases. However, the precise type and dose of exercise needed to accrue health benefits is a contentious issue with no clear consensus recommendations for the prevention of inactivity-related disorders and chronic diseases. Here we review some of the mechanisms responsible for improved skeletal muscle metabolic control and changes in cardiovascular function in response to low-volume HIT. We also consider the limited evidence regarding the potential application of HIT to people with, or at risk for, cardiometabolic disorders including type 2 diabetes. Finally, we provide insight on the utility of low-volume HIT for improving performance in athletes and highlight suggestions for future research.

Greene A, Grenier K, Aguileta M, Muise S, Farazifard R, Haque M, et al.  Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep. 2012;13:378–385.

Grueter CE, van Rooij E, Johnson BA, DeLeon SM, Sutherland LB, Qi X, et al.  A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell.
 
2012;149:671–683.

Haykowsky MJ, Brubaker PH, Stewart KP, Morgan TM, Eggebeen J, Kitzman DW.  Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction.  J Am Coll Cardiol.  2012 Jul;60(2):120-128.

Jin SM, Youle RJ.  PINK1- and Parkin-mediate mitophagy at a glance. J Cell Sci.  2012 Feb 15;125(4):795-799.
This study highlights the utility of HIT in inactive individuals, and suggests that it may be a viable alternative to traditionally prescribed continuous modalities of exercise for promoting self-efficacy and enjoyment of exercise. 

Laughlin MH, Bowles DK, Duncker DJ. The coronary circulation in exercise trainingAm J Physiol-Heart C. (2012) 302:H10–23.
Exercise training (EX) induces increases in coronary transport capacity through adaptations in the coronary microcirculation including increased arteriolar diameters and/or densities and changes in the vasomotor reactivity of coronary resistance arteries. The improved coronary capillary blood flow distribution appears to be the result of structural changes in the coronary tree and alterations in vasoreactivity of coronary resistance arteries. It is important to determine the mechanisms involved in these beneficial effects. 

Lin C-F, Huang T-H, Tu K-C, Lin LL, Tu Y-H, Yang R-S.  Acute effects of plyometric jumping and intermittent running on serum bone markers in young males.  Eur J Apply Physiol.  2012 Apr;112(4):1475-84.
The purpose of this study was to investigate whether different modes of single-bout exercise would cause different responses in short-term bone metabolism. 24 untrained male college students (19.1 ± 0.1 years old) were recruited and randomly assigned to three groups: (1) a single-bout plyometric exercise group (the PL group, n = 8), (2) a 200-meter × 10 intermittent running group (the IR group, n = 8) and (3) a sedentary control group, which followed the same time schedule of experimentation without performing any exercise (the CON group, n = 8). Exercises with different mechanical impact levels responded differently in serum bone formation markers as shown by osteocalcin. Because the increase in osteocalcin in the PL group was revealed shortly after the exercise bout, the changes might be due to an exercise-induced mechanical impact rather than bone cellular activities. 

Martinez TN, Greenamyre JT. Toxin models of mitochondrial dysfunction in Parkinson's diseaseAntioxid Redox Signal 2012;16:920–34.

Miller BF, Hamilton KL. A perspective on the determination of mitochondrial biogenesis. Am J Physiol Endocrinol Metab. 2012 Mar;302(5):E496–E499.

Paulsen G, Mikkelsen UR, Raastad T, Peake JM. Leucocytes, cytokines and satellite cells: what role do they play in muscle damage and regeneration following eccentric exercise? Exerc Immunol Rev2012;18:42–97.  

Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8:457–65.
During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases. 

Rämson R, Jürimäe J, Jürimäe T, Mäestu J.  The influence of increased training volume on cytokines and ghrelin concentration in college level male rowers.  Eur J Appl Physiol.  2008 Nov;104(5):839-46.

Sato T. Vitamin K2 and Bone Quality. Vitam Trace Elem. 2012:S6. doi:10.4172/2167-0390.S6-001.
Vitamin K is a cofactor required for post-translational gamma-carboxylation of vitamin K-dependent proteins, including coagulation and anti-coagulation factors; osteocalcin (OC), essential for bone metabolism; and matrix Gla proteins (MGP), an inhibitor of artery calcification. In addition to activation of OC, vitamin K2 induces collagen accumulation in the bone matrix. The principle effects of vitamin K on bone health are not to increase bone mineral density but to promote bone quality and bone strength. Vitamin K2, as menaquinone-7 (MK-7), is the only major vitamin K homolog which can activate OC at nutritional doses. The higher efficacy of MK-7 is due to its better bioavailability and longer half-life compared to other vitamin K homologs. Furthermore, a normal nutritional intake of MK-7 has been shown to activate MGP, which inhibit artery calcification, and has been associated with prevention of cardiovascular diseases. Thus, MK-7 is thought to contribute to calcium homeostasis in arteries as well as bones.

Shearer MJ, Fu X, Booth SL.  Vitamin K nutrition, metabolism, and requirements:  current concepts and future research.  Adv in Nutr.  2012;3(2):182-195.
In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for vitamin K, in large part because of a lack of robust endpoints that reflected adequacy of intake. Knowledge of the relative bioavailability of multiple vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of vitamin K in its free state and when incorporated into a plant matrix. In terms of clinical endpoints, vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for vitamin K prophylaxis in newborns, but the effectiveness of any vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lack of suitable biomarkers or clinical endpoints that can be used to determine vitamin K requirements among adults.

Sumida S, Iwamoto J, Kamide N, Otani T.  Evaluation of bone, nutrition, and physical function in Shorinji Kempo athletes.  Open Access J Sports Med.  2012;3:107-114.
The objectives of this study were to reveal the proportion of Shorinji Kempo athletes who had suffered fractures related to sports activities, and to evaluate bone mass, bone turnover, nutritional status, and physical function in these athletes. A medical examination was carried out for 16 Shorinji Kempo collegiate athletes. Seven athletes (43.8%) had experienced a sports-related traumatic fracture during Shorinji Kempo practice. Four athletes (25.0%) had a lower speed of sound (% young adult mean < 100%), and five athletes (31.3%) had higher levels of urinary cross-linked N-terminal telopeptides of type 1 collagen (a bone turnover marker) than the age-adjusted standard values. All the athletes had a lower daily calcium intake than the adequate intake, 12 (75.0%) had a lower daily vitamin D intake, and 15 (93.8%) had a lower daily vitamin K intake. Significant positive correlations were found between the vertical jump height, and the daily energy, and protein intakes. Results suggest that fractures are a common injury in Shorinji Kempo athletes, and that some athletes need to improve their bone mass, bone metabolism, and nutritional status in order to strengthen bone and improve physical function.

Thompson D, Karpe F, Lafontan M, Frayn K.  Physical activity and exercise in the regulation of human adipose tissue physiology.  Physiol Rev.  2012 Jan;92(1):157-91.
Physical activity and exercise are key components of energy expenditure and therefore of energy balance. Changes in energy balance alter fat mass. It is therefore reasonable to ask: What are the links between physical activity and adipose tissue function? There are many complexities. Epidemiological observations support the idea that physically active people have relatively low fat mass, and intervention studies tend to show that exercise training reduces fat mass. A much-discussed effect of exercise versus calorie restriction in preferentially reducing visceral fat is not borne out by meta-analyses. We conclude that, in addition to the regulation of fat mass, physical activity may contribute to metabolic health through beneficial dynamic changes within adipose tissue in response to each activity bout.

Vos M, Esposito G, Edirisinghe JN, Vilain S, Haddad DM, Slabbaert JR, et al.  Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency.  Science. 2012 June;336(6086):1306-10.
Human UBIAD1 localizes to mitochondria and converts vitamin K(1) to vitamin K(2). Vitamin K(2) is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Whether vitamin K(2) exerts a similar carrier function in eukaryotic cells is unknown. We identified Drosophila UBIAD1/Heix as a modifier of pink1, a gene mutated in Parkinson's disease that affects mitochondrial function. We found that vitamin K(2) was necessary and sufficient to transfer electrons in Drosophila mitochondria. Heix mutants showed severe mitochondrial defects that were rescued by vitamin K(2), and, similar to ubiquinone, vitamin K(2) transferred electrons in Drosophila mitochondria, resulting in more efficient adenosine triphosphate (ATP) production. Thus, mitochondrial dysfunction was rescued by vitamin K(2) that serves as a mitochondrial electron carrier, helping to maintain normal ATP production.

Weaver, CM. Calcium. In: Erdman JJ, Macdonald I, & Zeisel S. Editors.  2012.  Present Knowledge in Nutrition. 10th ed, pp. 434–446). Hoboken, NJ. Wiley-Blackwell.  p. 434-446.

Westenfeld R, Krueger T,  Schlieper G, Cranenburg C.M, Magdeleyns EJ, Heidenreich S,  et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: A randomized trial. Am J Kidney Dis. 2012;59:186–195.
Vascular calcification is a predictor of cardiovascular morbidity and mortality. Hemodialysis patients experience severe vascular calcifications. Matrix Gla protein (MGP) is a central calcification inhibitor of the arterial wall; its activity depends on vitamin K-dependent γ-glutamate carboxylation. Uncarboxylated MGP, formed as a result of vitamin K deficiency, is associated with cardiovascular disease. Recent studies suggest poor vitamin K status in hemodialysis patients. We therefore aimed to investigate whether daily vitamin K supplementation improves the bioactivity of vitamin K-dependent proteins in hemodialysis patients.  This study confirms that most hemodialysis patients have a functional vitamin K deficiency. More importantly, it is the first study showing that inactive MGP levels can be decreased markedly by daily vitamin K(2) supplementation. Our study provides the rationale for intervention trials aimed at decreasing vascular calcification in hemodialysis patients by vitamin K.

Yan L, DeMars LC, Johnson LK. Long-term voluntary running improves diet-induced adiposity in young adult mice. Nutr Res. 2012;32:458–465.

Baron R, Kneissel M.  WNT signaling in bone homeostasis and disease:  from human mutations to treatments.  Nat Med.  2013 Feb;19(2):179-92.

Beulens  JW, Booth SL, van den Heuvel EG, Stoecklin E, Baka A, Vermeer C.  The role of menaquinones (vitamin K₂) in human healthBritish J Nutrition.  2013;110(8):1357–1368.
Recent reports have attributed the potential health benefits of vitamin K beyond its function to activate hepatic coagulation factors. Moreover, several studies have suggested that menaquinones, also known as vitamin K2, may be more effective in activating extra-hepatic vitamin K-dependent proteins than phylloquinone, also known as vitamin K1. Nevertheless, present dietary reference values (DRV) for vitamin K are exclusively based on phylloquinone, and its function in coagulation. The present review describes the current knowledge on menaquinones based on the following criteria for setting DRV: optimal dietary intake; nutrient amount required to prevent deficiency, maintain optimal body stores and/or prevent chronic disease; factors influencing requirements such as absorption, metabolism, age and sex. There are significant gaps in the current knowledge on menaquinones based on the criteria for setting DRV. Therefore, we conclude that further investigations are needed to establish how differences among the vitamin K forms may influence tissue specificities and their role in human health. However, there is merit for considering both menaquinones and phylloquinone when developing future recommendations for vitamin K intake.

Boskey AL.  Bone composition:  relationship to bone fragility and antiosteoporotic drug effects.  Bonekey Rep.  2013;2:447.
The composition of a bone can be described in terms of the mineral phase, hydroxyapatite, the organic phase, which consists of collagen type I, noncollagenous proteins, other components and water. The relative proportions of these various components vary with age, site, gender, disease and treatment. Any drug therapy could change the composition of a bone. This review, however, will only address those pharmaceuticals used to treat or prevent diseases of bone: fragility fractures in particular, and the way they can alter the composition. It is suggested that while some of the antiosteoporotic drugs can and do modify composition, their positive effects on bone strength may be balanced by negative ones.

Dalmeijer GW, van der Schouw YT, Vermeer C. et al. Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy womenJ Nutr Biochem. 2013;24:624–8.
Matrix Gla protein (MGP) is a vitamin K-dependent protein and an inhibitor of vascular calcification. Vitamin K is required for the carboxylation of MGP and can thereby reduce calcification. Circulating MGP species with different conformations have been investigated as markers for coronary artery calcification (CAC). These results show that dp-ucMGP may serve as a biomarker of vitamin K status. Circulating dp-ucMGP and t-ucMGP may serve as markers for the extent of coronary artery calcification, but these findings need to be confirmed.

Egan, B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptationCell Metabol. 2013;17:162–184.
Preservation of aerobic fitness and skeletal muscle strength through exercise training can ameliorate metabolic dysfunction and prevent chronic disease. These benefits are mediated in part by extensive metabolic and molecular remodeling of skeletal muscle by exercise. Here, we review the metabolic responses and molecular mechanisms that underpin the adaptatation of skeletal muscle to acute exercise and exercise training.

Englund EK, Langham MC, Li C, Rodgers ZB, Floyd TF, Mohler ER, et al.  Combined measurement of perfusion, venous oxygen saturation, and skeletal muscle T2* during reactive hyperemia in the leg.  J Cardio Magnetic Res.  2013 Aug 19;15(70): https://doi.org/10.1186/1532-429X-15-70

Goiko M, Dierolf J, Gleberzon JS, Liao Y, Grohe B, Goldberg HA, et al.  Peptides of matrix Gla protein inhibit nucleation and growth of hydroxyapatite and calcium oxalate monohydrate crystals.  PLoS One.  2013;8(11):e80344.
Matrix Gla protein (MGP) is a phosphorylated and γ-carboxylated protein that has been shown to prevent the deposition of hydroxyapatite crystals in the walls of blood vessels. MGP is also expressed in kidney and may inhibit the formation of kidney stones, which mainly consist of another crystalline phase, calcium oxalate monohydrate. To determine the mechanism by which MGP prevents soft-tissue calcification, we have synthesized peptides corresponding to the phosphorylated and γ-carboxylated sequences of human MGP in both post-translationally modified and non-modified forms. The effects of these peptides on hydroxyapatite formation and calcium oxalate crystallization were quantified We demonstrated for the first time that MGP peptides inhibit the formation of calcium oxalate monohydrate. Based on the latter finding, we propose that MGP function not only to prevent blood-vessel calcification but also to inhibit stone formation in kidney.

Gomes, A, Price N, Ling A, Moslehi J, Montgomery M, Rajman L White J, Teodoro J, et al.   Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155:1624–1638.

Iqbal S, Ostojic O, Singh K, Joseph AM, and Hood DA. Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuseMuscle Nerve. 2013.48:963–970.
Chronic muscle use increases the ratio of fusion:fission proteins, leading to reticular mitochondria, whereas muscle disuse and aging result in a decrease in this ratio, culminating in fragmented organelles.

Kajimura D, Lee Hw, Riley KJ, Arteaga-Solis E, Ferron M, Zhou B, et al. Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell Metab. 2013;17:901–915. 

Klein-Nulend J, Bakker AD, Bacabac RG, Vatsa A, Weinbaum S.  Mechanosensation and transduction in osteocytes.  Bone.  2013 Jun;54(2):182-90.
The human skeleton is a miracle of engineering, combining both toughness and light weight. It does so because bones possess cellular mechanisms wherein external mechanical loads are sensed. These mechanical loads are transformed into biological signals, which ultimately direct bone formation and/or bone resorption. Osteocytes, since they are ubiquitous in the mineralized matrix, are the cells that sense mechanical loads and transduce the mechanical signals into a chemical response. The osteocytes then release signaling molecules, which orchestrate the recruitment and activity of osteoblasts or osteoclasts, resulting in the adaptation of bone mass and structure. In this review, we highlight current insights in bone adaptation to external mechanical loading, with an emphasis on how a mechanical load placed on whole bones is translated and amplified into a mechanical signal that is subsequently sensed by the osteocytes.

Konopka, AR, and Sreekumaran Nair K. Mitochondrial and skeletal muscle health with advancing age. Mol Cell Endocrinol. 2013;379:19–29
The focus of this review was to discuss promising human physiological systems underpinning the decline of mitochondrial and skeletal muscle health with advancing age while highlighting therapeutic strategies such as aerobic exercise and caloric restriction for combating age-related functional impairments.

Knapen M, Drummen N, Smit E, Vermeer, C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013, 24, 2499–2507.
Healthy postmenopausal women (n = 244) received for 3 years placebo or MK-7 (180 μg MK-7/day) capsules. Bone mineral density of lumbar spine, total hip, and femoral neck was measured by DXA; bone strength indices of the femoral neck were calculated. Vertebral fracture assessment was performed by DXA and used as measure for vertebral fractures. Circulating uncarboxylated osteocalcin (ucOC) and carboxylated OC (cOC) were measured; the ucOC/cOC ratio served as marker of vitamin K status. Measurements occurred at baseline and after 1, 2, and 3 years of treatment.  They found that MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae.

Mao K, Klionsky D. Mitochondrial fission facilitates mitophagy in Saccharomyces cerevisiae. Autophagy. 2013;9:1900–1901.

Michelsen J, Wallaschofski H, Friedrich N, Spielhagen C, Rettig R, Ittermann T.  Reference intervals for serum concentrations of three bone turnover markers for men and women.  Bone.  2013 Dec;57(2):399-404.

Mizokami, A. et al. Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice. PLoS ONE. 2013;8:e57375.

Misra D, Booth SL, Tolstykh I, Felson DT, Nevitt MC, Lewis CE, et al.  Vitamin K deficiency is associated with incident knee osteoarthritis. Am J Med2013;126:243–8.
In the first such longitudinal study, subclinical vitamin K deficiency was associated with increased risk of developing radiographic knee osteoarthritis and MRI-based cartilage lesions. Further study of vitamin K is warranted given its therapeutic/prophylactic potential for osteoarthritis.

Neve A, Corrado A, Cantatore FP.  Osteocalcin: skeletal and extra-skeletal effects. J Cell Physiol, 2013;228(6):1149-53.
This review highlights the recent studies concerning skeletal and extra-skeletal effects of OC.  Osteocalcin (OC) is a non-collagenous, vitamin K-dependent protein secreted in the late stage of osteoblasts differentiation. The presence of the three residues of γ-carbossiglutamatic acid, specific of the active form of OC protein, allows the protein to bind calcium and consequently hydroxyapatite. The dual role of OC in bone can be presumed as follows: firstly, OC acts as a regulator of bone mineralization; secondly, OC regulates osteoblast and osteoclast activity. Recently the metabolic activity of OC, restricted to the un-carboxylated form has been demonstrated in osteoblast-specific knockout mice. This effect is mediated by the regulation of pancreatic β-cell proliferation and insulin secretion and adiponectin production by adipose tissue and leads to the regulation of glucose metabolism and fat mass. Further investigations in humans are required to demonstrate the role of OC in the regulation of human energy metabolism. Moreover, it is presumable that OC also acts on blood vessels by inducing angiogenesis and pathological mineralization.

Schurgers LJ, Uitto J, Reutelingsperger CP.  Vitamin K-dependent carboxylation of matrix Gla-protein:  a crucial switch to control ectopic mineralization.  Trends Mol Med.  2013;19:217-226.
Vascular mineralization has recently emerged as a risk factor for cardiovascular morbidity and mortality. Previously regarded as a passive end-stage process, vascular mineralization is currently recognized as an actively regulated process with cellular and humoral contributions. The discovery that the vitamin K-dependent matrix Gla-protein (MGP) is a strong inhibitor of vascular calcification has propelled our mechanistic understanding of this process and opened novel avenues for diagnosis and treatment. This review focuses on molecular mechanisms of vascular mineralization involving MGP and discusses the potential for treatments and biomarkers to monitor patients at risk for vascular mineralization.

Sibonga JD.  Spaceflight-induced bone loss: is there an osteoporosis risk? Curr Osteoporos Rep. 2013;11(2):92–98. 
Currently, the measurement of areal bone mineral density (aBMD) is used at NASA to evaluate the effects of spaceflight on the skeletal health of astronauts. Notably, there are precipitous declines in aBMD with losses >10 % detected in the hip and spine in some astronauts following a typical 6-month mission in space. How those percentage changes in aBMD relate to fracture risk in the younger-aged astronaut is unknown. Given the unique set of risk factors that could be contributing to this bone loss (eg, adaptation to weightlessness, suboptimal diet, reduced physical activity, perturbed mineral metabolism), one might not expect skeletal changes due to spaceflight to be similar to skeletal changes due to aging. Following a brief review of the current knowledge-base, this paper will discuss some innovative research projects being pursued at NASA to help understand skeletal health in astronauts.

Arfat Y, Xiao W-Z, Iftikhar S, Zhao F, Li D-J, Sun Y-L, et al.  Physiological effects of microgravity on bone cells.  Calc Tissue Int.  2014;94:569-579.
Life on Earth developed under the influence of normal gravity (1g). Scientists have suggested that normal physiological processes, such as the functional integrity of muscles and bone mass, can be affected by microgravity during spaceflight. During the life span, bone not only develops as a structure designed specifically for mechanical tasks but also adapts for efficiency. The lack of weight-bearing forces makes microgravity an ideal physical stimulus to evaluate bone cell responses. One of the most serious problems induced by long-term weightlessness is bone mineral loss. Results from in vitro studies that entailed the use of bone cells in spaceflights showed modification in cell attachment structures and cytoskeletal reorganization, which may be involved in bone loss. Humans exposed to microgravity conditions experience various physiological changes, including loss of bone mass, muscle deterioration, and immunodeficiency. The objective of this review is to summarize the recent research on bone cells under microgravity conditions based on advances in the field.

Azuma K, Ouchi Y, Inoue S.  Vitamin K: novel molecular mechanisms of action and its roles in osteoporosis.  Geriatr Gerontol Int.  2014 Jan;14(1):1-7.
Vitamin K is a fat-soluble vitamin, which is involved in blood coagulation. Vitamin K also has extrahepatic actions and has been shown to prevent bone fractures in clinical studies. In addition, epidemiological studies suggest that a lack of vitamin K is associated with several geriatric diseases, including osteoporosis, osteoarthritis, dementia and arteriosclerosis. It has also been shown that vitamin K contributes to the prevention and treatment of some kinds of malignancies. Recently, we discovered a novel role for vitamin K as a ligand of the nuclear receptor, steroid and xenobiotic receptor (SXR), and its murine ortholog, pregnane X receptor (PXR). In addition to its established roles as a cofactor of γ-glutamyl carboxylase (GGCX) in mediating post-transcriptional modifications, vitamin K has a different mode of action mediated by transcriptional regulation of SXR/PXR target genes. The discoveries of a novel mode of vitamin K action have opened up new possibilities that vitamin K might be useful for prevention or treatment of a variety of diseases that affect the geriatric population.

Bishop DJ, Granata C, Eynon N.  Can we optimize the exercise training prescription to maximise improvements in mitochondria function and content?  Biochim Biophys Acta. 2014 Apr;1840(4):1266-75.
This review will focus predominantly on the effects of exercise on mitochondrial function and content.  The results of cross-sectional studies, as well as training studies involving rats and humans, suggest that training intensity may be an important determinant of improvements in mitochondrial function (as determined by mitochondrial respiration), but not mitochondrial content (as assessed by citrate synthase activity). In contrast, it appears that training volume, rather than training intensity, may be an important determinant of exercise-induced improvements in mitochondrial content. Exercise-induced mitochondrial adaptations are quickly reversed following a reduction or cessation of physical activity, highlighting that skeletal muscle is a remarkably plastic tissue. Further research is also required to better understand how genetic variants influence the large individual variability for exercise-induced changes in mitochondrial biogenesis.

Boushel R, Lundby C, Qvortrup K, Sahlin K.  Mitochondrial plasticity with exercise training and extreme environments.  Exercise and Sport Sciences Reviews.  2014;42(4):169-174.
Mitochondria form a reticulum in skeletal muscle. Exercise training stimulates mitochondrial biogenesis, yet an emerging hypothesis is that training also induces qualitative regulatory changes. Substrate oxidation, oxygen affinity, and biochemical coupling efficiency may be regulated differentially with training and exposure to extreme environments. Threshold training doses inducing mitochondrial upregulation remain to be elucidated considering fitness level.

Brotto M, Johnson ML.  Endocrine crosstalk between muscle and bone. Curr Osteoporos Rep.  2014;12:135-141.
The musculoskeletal system is a complex organ comprised of the skeletal bones, skeletal muscles, tendons, ligaments, cartilage, joints, and other connective tissue that physically and mechanically interact to provide animals and humans with the essential ability of locomotion. This mechanical interaction is undoubtedly essential for much of the diverse shape and forms observed in vertebrates and even in invertebrates with rudimentary musculoskeletal systems such as fish. The mechanical theories of musculoskeletal development have had tremendous influence of our understanding of biology, because these relationships are clear and palpable. Less visible to the naked eye or even to the microscope is the biochemical interaction among the individual players of the musculoskeletal system. It was only in recent years that we have begun to appreciate that beyond this mechanical coupling of muscle and bones, these 2 tissues function at a higher level through crosstalk signaling mechanisms that are important for the function of the concomitant tissue. Our brief review attempts to present some of the key concepts of these new concepts and outline to present muscles and bones as secretory/endocrine organs, the evidence for mutual genetic and tissue interactions, pathophysiological examples of crosstalk, and the exciting new directions for this promising field of research aimed at understanding the biochemical/molecular coupling of these 2 intimately associated tissues.

Caluwe R, Vandecasteele S, Van Vlem B, Vermeer D, De Vriese AS.  Vitamin K2 supplementaiton in haemodialysis patients:  a randomized dose-finding study.  Nephrol Dial Transplant.  2014 Jul;29(7):1385-90.
Chronic haemodialysis patients have high levels of inactive MGP, possibly related to a low dietary vitamin K intake. Pharmacological doses of MK-7 dose-dependently reduce dp-uc-MGP. Menaquinone supplementation may be a novel approach to prevent vascular calcifications in chronic haemodialysis patients.

Gouspillou G, Sgarioto N, Kapchinsky S, Purves-Smith F, Norris B, Pion CH, Barbat-Artigas S, Lemieux F, Taivassalo T, Morais JA, et al.  Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humansFASEB J. 2014;28:1621–1633.
Mitochondrial dysfunction is implicated in skeletal muscle atrophy and dysfunction with aging, with strong support for an increased mitochondrial-mediated apoptosis in sedentary rodent models. We examined mitochondrial function [respiration, reactive oxygen species (ROS) emission, and calcium retention capacity (CRC)] in permeabilized myofibers obtained from vastus lateralis muscle biopsies of healthy physically active young and older men. Collectively, these results show that mitochondrial-mediated apoptotic signaling is increased in older human muscle and suggest that accumulation of dysfunctional mitochondria with exaggerated apoptotic sensitivity is due to impaired mitophagy.

Gupte AA, Sabek OM, Fraga D, Minze LJ, Nishimoto SK, Liu JZ, et al. Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome. Endocrinology. 2014;155:4697–4705.

Hoier B, Hellsten Y.  Exercise-induced capillary growth in human skeletal muscle and the dynamics of VEGF.  Microcirculation.  2014 May;21(4):301-315.
In skeletal muscle, growth of capillaries is an important adaptation to exercise training that secures adequate diffusion capacity for oxygen and nutrients even at high-intensity exercise when increases in muscle blood flow are profound. Mechanical forces present during muscle activity, such as shear stress and passive stretch, lead to cellular signaling, enhanced expression of angiogenic factors, and initiation of capillary growth. The most central angiogenic factor in skeletal muscle capillary growth is Vascular Endothelial Growth Factor (VEGF). During muscle contraction, VEGF increases in the muscle interstitium, acts on VEGF receptors on the capillary endothelium, and thereby stimulates angiogenic processes. A primary source of muscle interstitial VEGF during exercise is the skeletal muscle fibers which contain large stores of VEGF within vesicles. Future studies should focus on elucidating mechanisms and regulation of VEGF secretion.

Jung ME, Bourne JE, Little JP.  Where does HIT fit?  An examination of the affective response to high-intensity intervals in comparison to continuous moderate-and continuous vigorous-intensity exercise in the exercise intensity-affect continuum.  PLoS One. 2014 Dec 8;9(12):e114541.
This study highlights the utility of HIT in inactive individuals, and suggests that it may be a viable alternative to traditionally prescribed continuous modalities of exercise for promoting self-efficacy and enjoyment of exercise.

Koitaya N, Sekiguchi M, Tousen Y, Nishide Y, Morita A, Yamauchi J, et al.  Low-dose vitamin K2 (MK4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women.  J Bone Miner Metab.  2014 Mar;32(2):152-50.
Menaquinone-4 (MK-4) administered at a pharmacological dosage of 45 mg/day has been used for the treatment of osteoporosis in Japan. However, it is not known whether a lower dose of MK-4 supplementation is beneficial for bone health in healthy postmenopausal women. The aim of this study was to examine the long-term effects of 1.5-mg daily supplementation of MK-4 on the various markers of bone turnover and bone mineral density (BMD). The study was performed as a randomized, double-blind, placebo-controlled trial. The participants (aged 50-65 years) were randomly assigned to one of two groups according to the MK-4 dose received: the placebo-control group (n = 24) and the 1.5-mg MK-4 group (n = 24). These results suggest that low-dose MK-4 supplementation for 6-12 months improved bone quality in the postmenopausal Japanese women by decreasing the serum ucOC and pentosidine concentrations, without any substantial adverse effects.

Liesa M, Palacin M, Zorzano A.  Mitochondrial dynamics in mammalian health and disease.  Physiol Rev.  2009 Jul;89(3):799-845.
Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. These findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.

Levinger I, Scott D, Nicholson GC, Stuart AL, Duque G, McCorquodale T, Herrmann M, et al.  Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women.  Bone. 2014 Jul;65:8-12.
We investigated the association between undercarboxylated osteocalcin (ucOC) and lower-limb muscle strength in women over the age of 70 years. The study also aimed to confirm the association between bone turnover markers and heel ultrasound measures. A post-hoc analysis using data collected as part of a randomized placebo-controlled trial of vitamin D supplementation. In conclusion, ucOC% is positively associated with muscle strength and negatively associated with α-ACT. These data support a role for ucOC in musculoskeletal interactions in humans. Whilst total OC is associated with bone health, ucOC% and ucOC may also be linked to falls and fracture risk by influencing muscle function.

Levinger I, Jerums G, Stepto NK, Parker L, Serpiello FR, et al.  The effect of acute exercise on undercarboxylated osteocalcin and insulin sensitivity in obese men.  JBMR.  2014 Dec;29(12):2571-2576.
Acute exercise improves insulin sensitivity for hours after the exercise is ceased. The skeleton contributes to glucose metabolism and insulin sensitivity via osteocalcin (OC) in its undercarboxylated (ucOC) form in mice. We tested the hypothesis that insulin sensitivity over the hours after exercise is associated with circulating levels of ucOC. Blood samples and five muscle biopsies were obtained; two at the resting-control session, one before and one after clamping, and three in the exercise session, at rest, 60 minutes after exercise, and after the clamp. Exercise increased serum ucOC but not total OC.  Blood glucose was ∼6% lower and insulin sensitivity was ∼35% higher after exercise compared with control (both p < 0.05). In a multiple-linear regression including BMI, age, and aerobic fitness, ucOC was associated with whole-body insulin sensitivity at rest and after exercise. Insulin sensitivity, after acute exercise, is associated with circulating levels of ucOC in obese men.

Matsouka S, Kennedy AJ, dos Santos EGD, Tomazela AL, Rubio LCS.  Energy cane:  its concept, development, characteristics, and prospects.  Advances in Botany.  2014;2014:https://doi.org/10.1155/2014/59727

Mishra P, Chan D.  Mitochondrial dynamics and inheritance during cell division, development and disease.  Nat Rev Mol Cell Biol.  2014;15:634-46.

Nakamura E, Aoki M, Watanabe F, Kamimura A.  Low-dose menaquinone-4 improves gamma-carboxylation of osteocalcin in young males:  a non-placebo-controlled dose-response study.  Nutr J.  2014;13:85.
Fifteen healthy males aged 25 years (median) participated in a non-placebo-controlled dose-examination study.  They received MK4 daily for five weeks at 0, 300, 600, 900, and 1500 ug/day in weeks 1,2,3,4, and 5, respectively. Compared to baseline, serum y-carboxylated OC levels were significantly greater at an intake of 900 ug/day or more.. serum ucOC levels and the ratio of serum ucOC to y-carboxylated OC were significantly lower than baseline at doess of 600 ug/day.

Pal M, Febbraio MA, Whitham M.  From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol. 2014;92:331–9.
The lack of physical activity and overnutrition in our modern lifestyle culminates in what we now experience as the current obesity and diabetes pandemic. Medical research performed over the past 20 years identified chronic low-grade inflammation as a mediator of these metabolic disorders. Hence, finding therapeutic strategies against this underlying inflammation and identifying molecules implicated in this process is of significant importance.  We review here the literature considering the complex, pleiotropic role of IL-6 in the context of metabolism in health and disease.

Palikaras K, Tavernarakis N.  Mitochondrial homeostasis:  the interplay between mitophagy and mitochondrial biogenesis.   Exp Gerontol.  2014 Aug:56:182-8.
Mitochondria are highly dynamic organelles and their proper function is crucial for the maintenance of cellular homeostasis. Mitochondrial biogenesis and mitophagy are two pathways that regulate mitochondrial content and metabolism preserving homeostasis. The tight regulation between these opposing processes is essential for cellular adaptation in response to cellular metabolic state, stress and other intracellular or environmental signals. Interestingly, imbalance between mitochondrial proliferation and degradation process results in progressive development of numerous pathologic conditions. Here we review recent studies that highlight the intricate interplay between mitochondrial biogenesis and mitophagy, mainly focusing on the molecular mechanisms that govern the coordination of these processes and their involvement in age-related pathologies and aging.

Psilander N. 2014 Nov 21.  The effect of different exercise regimens on mitochondrial biogenesis and performance. Stockholm, Sweden:Inst för fysiologi och farmakologi/Dept of Physiology and Pharmacology. 61 pages. 
Endurance training is a powerful tool to improve both health and performance. Physical activity is now recognized as an effective treatment and prevention therapy for a wide range of diseases. One of the most profound adaptations to endurance training is increased mitochondrial function and content within the exercising muscles. Mitochondrial quality and quantity are closely related to several of the positive health effects reported after training. High mitochondrial content strongly correlates with muscle oxidative capacity and endurance performance. Even though it is well known that endurance training increases mitochondrial content, it is unclear which type of training is the most efficient to promote mitochondrial biogenesis. Therefore, the basis for current exercise recommendations relative to mitochondrial biogenesis is poor or absent. Thus, the main objective of this thesis was to evaluate the effect of different training strategies on mitochondrial biogenesis.

Scalzo RL, Peltonen GL, Binns SC, Shankaran M, Giordano GR, Hartley DA.  Greater muscle protein synthesis and mitochondrial biogenesis in males compared with females during spring interval training.  FASEB.  2014 Jun;28(6):2705-14.
Improved endurance exercise performance in adult humans after sprint interval training (SIT) has been attributed to mitochondrial biogenesis. However, muscle protein synthesis (MPS) and mitochondrial biogenesis during SIT have not been measured, nor have sex-specific differences. The researchers hypothesized that males and females would have similar rates of MPS, mitochondrial biogenesis, and synthesis of individual proteins during SIT. For the first time, they documented greater MPS and mitochondrial biogenesis during SIT in males than in females and describe the synthetic response of individual proteins in humans during exercise training.

Sims NA, Martin TJ. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bone Key Rep. 2014;3:481.
Coupling between bone formation and bone resorption refers to the process within basic multicellular units in which resorption by osteoclasts is met by the generation of osteoblasts from precursors, and their bone-forming activity, which needs to be sufficient to replace the bone lost. There are many sources of activities that contribute to coupling at remodeling sites, including growth factors released from the matrix, soluble and membrane products of osteoclasts and their precursors, signals from osteocytes and from immune cells and signaling taking place within the osteoblast lineage. In this review, we explore the potential roles of a number of these factors, including sphingosine-1-phosphate, semaphorins, ephrins, interleukin-6 (IL-6) family cytokines and marrow-derived factors. Their interactions achieve the essential tight control of coupling within individual remodeling units that is required for control of skeletal mass.

Willems BA, Vermeer C, Reutelingsperger CP, Schurgers LJ. The realm of vitamin K dependent proteins: shifting from coagulation toward calcification. Mol Nutr Food Res2014;58:1620–1635.
In the past few decades vitamin K has emerged from a single-function "haemostasis vitamin" to a "multi-function vitamin." The use of vitamin K antagonists (VKA) inevitably showed that the inhibition was not restricted to vitamin K dependent coagulation factors but also synthesis of functional extrahepatic vitamin K dependent proteins (VKDPs), thereby eliciting undesired side effects. Vascular calcification is one of the recently revealed detrimental effects of VKA. The discovery that VKDPs are involved in vascular calcification has propelled our mechanistic understanding of this process and has opened novel avenues for diagnosis and treatment. This review addresses mechanisms of VKDPs and their significance for physiological and pathological calcification.

Baccaro LF, Conde DM, Costa-Paiva L, Pinto-Neto AM.  The epidemiology and management of postmenopausal osteoporosis: a viewpoint from Brazil. Clin Interv Aging. 2015;10:583–591.   
Brazil has an aging population, with an associated increase in the prevalence of chronic diseases. Postmenopausal osteoporosis is of particular concern because it leads to an increased risk of fractures, with subsequent negative impacts on health in older women. In recent years, efforts have been made to better understand the epidemiology of osteoporosis in Brazil, and to manage both direct and indirect costs to the Brazilian health care system. The reported prevalence of osteoporosis among postmenopausal women in Brazil varies from 15% to 33%, depending on the study methodology and the use of bone densitometry data or self-reporting by participants.

Goodman CA, Hornberger TA, Robling AG.  Bone and skeletal muscle: key players in mechanotransduction and potential overlapping mechanisms. Bone.  2015;80:24–36. 
The development and maintenance of skeletal muscle and bone mass is critical for movement, health and issues associated with the quality of life. Skeletal muscle and bone mass are regulated by a variety of factors that include changes in mechanical loading. Moreover, bone mass is, in large part, regulated by muscle-derived mechanical forces and thus by changes in muscle mass/strength. A thorough understanding of the cellular mechanism(s) responsible for mechanotransduction in bone and skeletal muscle is essential for the development of effective exercise and pharmaceutical strategies aimed at increasing, and/or preventing the loss of, mass in these tissues. Thus, in this review we will attempt to summarize the current evidence for the major molecular mechanisms involved in mechanotransduction in skeletal muscle and bone.

Joyner MJ, Casey DP. Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needsPhysiol Rev. 2015;95:549–601.
This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans.

Lombardi G, Perego S, Luzi L, Banfi G.  A four-season molecule: osteocalcin. Updates in its physiological roles.  Endocrine.  2015; Mar;48(2):394-404.
Osteocalcin (OC) is the main non-collagenous hydroxyapatite-binding protein synthesized by osteoblasts, odontoblasts, and hypertrophic chondrocytes. It has a regulatory role in mineralization and it is considered a marker of bone cell metabolism. Recent findings evidenced new extra-skeletal roles for OC, depicting it as a real hormone. There are evidences linking OC, and the bone metabolism, with a series of endocrine (glucose metabolism, energy metabolism, fertility) physiological (muscle activity) and pathological functions (ectopic calcification). Aim of this review is to give a full overview of the physiological roles of OC by collecting the newest experimental findings on this intriguing molecule.

Shea MK, Cushman M, Booth SL, Burke GL, Chen H, Kritchevsky SB. Associations between vitamin K status and haemostatic and inflammatory biomarkers in community-dwelling adults. Thromb Haemost. 2014;112:438–444.
Vitamin K is integral to haemostatic function, and in vitro and animal experiments suggest that vitamin K can suppress production of inflammatory cytokines. To test the hypothesis that higher vitamin K status is associated with lower haemostatic activation and inflammation in community-dwelling adults, we analysed the cross-sectional association between serum phylloquinone (vitamin K1) with haemostatic and inflammatory biomarkers in 662 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) [mean (SD) age=62 (10) years; 46% female; 37% Caucasian, 25% African-American, 25% Hispanic, 13% Chinese-American]. We detected an interaction between age and serum phylloquinone with respect to factor VIII and D-dimer. Among participants ≥70 years, serum phylloquinone was inversely associated with factor VIII activity (p-trend=0.06) and positively associated with D-dimer (p-trend=0.01) but was not associated with either marker among participants <70 years (both p≥0.38). In contrast, dietary phylloquinone intake was not associated with any inflammatory or haemostatic biomarker evaluated (all p-trend>0.11). These findings are consistent with laboratory-based studies that suggest a possible anti-inflammatory role for vitamin K.

Anaraki, PK, Patecki M, Tkachuk S, Kiyan Y, Haller H, Dumler I. Urrokinase receptor mediates osteoclastogenesis via M-CSF release from osteoblasts and the c-Fms/PI3K/Akt/NF-κB pathway in osteoclasts. J Bone Min Res. 2015;30:379–388.

DiNicolantonio JJ, Bhutani J, O’Keefe JH.  The health benefits of vitamin K.  Open Heart.  2015;2(1):e000300.
Vitamin K has important functions within the body, some of which are still being discovered. Research has shown that vitamin K is an anticalcification, anticancer, bone-forming and insulin-sensitising molecule. Recent data indicate that subclinical vitamin K deficiency is not uncommon. Additionally, vitamin K antagonists such as warfarin may cause detrimental side effects, which may partly be blunted through vitamin K supplementation.

Drake J, Wilson RJ, Yan Z.  Molecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle.  FASEB Journal.  2015 Sept;30(1):13-22.
Exercise training enhances physical performance and confers health benefits, largely through adaptations in skeletal muscle. Mitochondrial adaptation, encompassing coordinated improvements in quantity (content) and quality (structure and function), is increasingly recognized as a key factor in the beneficial outcomes of exercise training. Exercise training has long been known to promote mitochondrial biogenesis, but recent work has demonstrated that it has a profound impact on mitochondrial dynamics (fusion and fission) and clearance (mitophagy), as well. In this review, we discuss the various mechanisms through which exercise training promotes mitochondrial quantity and quality in skeletal muscle. 

Faienza MF, Luce V, Ventura A, Colaianni G, Colucci S, Cavallo L, et al.  Skeleton and glucose metabolism:  a bone-pancreas loop.  Int J Endrocrinol.  2015; 2015:758148.
Bone has been considered a structure essential for mobility, calcium homeostasis, and hematopoietic function. Recent advances in bone biology have highlighted the importance of skeleton as an endocrine organ which regulates some metabolic pathways, in particular, insulin signaling and glucose tolerance. This review will point out the role of bone as an endocrine "gland" and, specifically, of bone-specific proteins, as the osteocalcin (Ocn), and proteins involved in bone remodeling, as osteoprotegerin, in the regulation of insulin function and glucose metabolism.

Glancy B, Hartnell LM, Malide D, Yu ZX, Combs CA, Connelly PS, et al.  Mitochondrial reticulum for cellular energy distribution in muscle.  Nature.  2015;523;617-20.
We propose that membrane potential conduction via the mitochondrial reticulum is the dominant pathway for skeletal muscle energy distribution.

Huang Z-B, Wan S-L, Lu Y-J, Ning L, Liu C, Fan S-W.  Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women:  a meta-analysis of randomized controlled trials.  Osteoporos Int.  2015 Mar;26(3):1175-1186.
To identify the role of vitamin K2 for the prevention and treatment of osteoporosis in postmenopausal women, we conducted this meta-analysis of 19 randomized controlled trials. Our results showed that vitamin K2 might play a role in maintaining the bone mineral density and in reducing the incidence of fractures for postmenopausal women with osteoporosis. This meta-analysis seemed to support the hypothesis that vitamin K2 plays kind of a role in the maintenance and improvement of vertebral BMD and the prevention of fractures in postmenopausal women with osteoporosis. The reduction of undercarboxylated osteocalcin and increment of osteocalcin may have some relation to the process of bone mineralization. Further high-quality RCTs with large sample size are needed to confirm the role of vitamin K2 in osteoporosis for postmenopausal women.

Joyner MJ, Casey DP. Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needsPhysiol Rev.  2015;95: 549–601.
This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans.

Inaba N, Sato T, Yamashita T.  Low-dose daily intake of vitamin K(2) (Menaquinone-7) improves osteocalcin γ-carboxylation:  a double-blind, randomized controlled trials.  J Nutr Sci Vitaminol.  2015;61(6):471-80. 
Vitamin K is essential for bone health, but the effects of low-dose vitamin K intake in Japanese subjects remain unclear. They investigated the effective minimum daily menaquinone-7 dose for improving osteocalcin γ-carboxylation. Study 1 was a double-blind, randomized controlled dose-finding trial; 60 postmenopausal women aged 50-69 y were allocated to one of four dosage group and consumed 0, 50, 100, or 200 μg menaquinone-7 daily for 4 wk, respectively, with a controlled diet in accordance with recommended daily intakes for 2010 in Japan. Study 2 was a double-blind, randomized placebo-controlled trial based on the results of Study 1; 120 subjects aged 20-69 y were allocated to the placebo or MK-7 group and consumed 0 or 100 μg menaquinone-7 daily for 12 wk, respectively. In both studies, circulating carboxylated osteocalcin and undercarboxylated osteocalcin were measured. They concluded that daily menaquinone-7 intake ≥100 μg was suggested to improve osteocalcin γ-carboxylation.

Kennel PJ, Mancini DM, Schulze PC.  Skeletal muscle changes in chronic cardiac disease and failure.  Compr Physiol.  2015 Sep 20;5(4):1947-1969.
Peak exercise performance in healthy man is limited not only by pulmonary or skeletal muscle function but also by cardiac function. Thus, abnormalities in cardiac function will have a major impact on exercise performance. Many cardiac diseases affect exercise performance and indeed for some cardiac conditions such as atherosclerotic heart disease, exercise testing is frequently used not only to measure functional capacity but also to make a diagnosis of heart disease, evaluate the efficacy of treatment, and predict prognosis. Early in the course of cardiac diseases, exercise performance will be minimally affected but with disease progression impairment in exercise capacity will become apparent. Ejection fraction, that is, the percent of blood volume ejected with each cardiac cycle is often used as a measure of cardiac performance but frequently there is a dissociation between the ejection fraction and exercise capacity in patients with heart disease. The focus of this work will be on patients with systolic heart failure as the incidence and prevalence of heart failure is reaching epidemic proportions and heart failure is the end result of many other chronic cardiac diseases. The prognostic role of exercise and benefits of exercise training will also be discussed.

Knapen MHJ, Braam LAJLM, Drummen NE, Bekers O, Hoeks APG, Vermeer C.  Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women.  A double-blind randomized clinical trial.  2015 Feb 19;113(5):1135-44.
This study investigated long-term effects of MK-7 (180 µg/day) supplementation on arterial stiffness in a double-blind, placebo-controlled trial. Healthy postmenopausal women received either placebo or MK-7 for three years. Indices of local carotid stiffness were measured by echotracking. Circulating desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP) as well as acute phase markers Interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α) and markers for endothelial dysfunction Vascular Cell Adhesion Molecule (VCAM), E-selectin, and Advanced Glycation Endproducts (AGEs) were measured. In conclusion, long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness.

Liu Y-P, Gu Y-M, Thijs, L, Knapen MHJ, Salvi E, Citterio L, et al.   Inactive Matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population. Hypertension 2015, 65, 463–470.
Matrix Gla-protein is a vitamin K-dependent protein that strongly inhibits arterial calcification. Vitamin K deficiency leads to production of inactive nonphosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP). In a Flemish population study, we measured circulating dp-ucMGP at baseline (1996-2011), genotyped MGP, recorded adverse health outcomes until December 31, 2012, and assessed the multivariable-adjusted associations of adverse health outcomes with dp-ucMGP. They found that higher dp-ucMGP (vitamin K deficiency) predicts total, non-cancer and cardiovascular mortality, but lower coronary risk.

Lombardi G, Ziemann E, Banfi G.  Physical activity and bone health:  what is the role of immune system?  A narrative review of the third way.  Front Endocrinol.  2019;10:60.
Bone tissue can be seen as a physiological hub of several stimuli of different origin (e.g., dietary, endocrine, nervous, immune, skeletal muscle traction, biomechanical load). The aim of this narrative review is to give a complete view of the exercise-dependent immune system-mediated effects on bone metabolism and function.

Maresz K.  Proper calcium use:  vitamin K2 as a promoter of bone and cardiovascular health.  Integrative Medicine; 2015;14(1):34-39.
Inadequate calcium intake can lead to decreased bone mineral density, which can increase the risk of bone fractures. Supplemental calcium promotes bone mineral density and strength and can prevent osteoporosis. Recent scientific evidence, however, suggests that elevated consumption of calcium supplements may raise the risk for heart disease and can be connected with accelerated deposit of calcium in blood-vessel walls and soft tissues. In contrast, vitamin K2 is associated with the inhibition of arterial calcification and arterial stiffening. An adequate intake of vitamin K2 has been shown to lower the risk of vascular damage because it activates matrix GLA protein (MGP), which inhibits the deposits of calcium on the walls. Vitamin K, particularly as vitamin K2, is nearly nonexistent in junk food, with little being consumed even in a healthy Western diet. Vitamin K deficiency results in inadequate activation of MGP, which greatly impairs the process of calcium removal and increases the risk of calcification of the blood vessels. An increased intake of vitamin K2 could be a means of lowering calcium-associated health risks.

Ogasawara J, Izawa T, Sakurai T, Sakurai T, Shirato K, Ishibashi Y, Ishida H, Ohno H, Kizaki T. The molecular mechanism underlying continuous exercise training-induced adaptive changes of lipolysis in white adipose cells. J Obesity. 2015;473430. 
Physical exercise accelerates the mobilization of free fatty acids from white adipocytes to provide fuel for energy. This happens in several tissues and helps to regulate a whole-body state of metabolism. This review outlines the alterations in the lipolytic molecules of white adipocytes that result from ET, which includes the molecular regulation of TG lipases through the lipolytic cascade.

Otani, T, et al. Signaling pathway for adiponectin expression in adipocytes by osteocalcin. Cell Signal.  2015;27:532–544.
In addition to providing skeletal support, the bone is an endocrine organ that produces osteocalcin, whose uncarboxylated form (GluOC) increases insulin secretion either directly or indirectly by promoting incretin secretion. Our results have thus revealed the signaling pathway by which GluOC induces adiponectin expression in adipocytes.

Pivin E, Ponte B, Pruijm M, Ackermann D, Guessous I, Ehret G et al.  Inactive matrix Gla-protein is associated with arterial stiffness in an adult population-based study.  Hypertension. 2015 Jul;66(1):85-92.
Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor of mortality. Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular markers, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP are associated with increased PWV. We recruited participants via a multicenter family-based cross-sectional study in Switzerland.  In conclusion, high levels of dp-ucMGP are independently and positively associated with arterial stiffness after adjustment for common cardiovascular risk factors, renal function, and age. Experimental studies are needed to determine whether vitamin K supplementation slows arterial stiffening by increasing MGP carboxylation.

Platt C, Houstis N, Rosenzweig A. Using exercise to measure and modify cardiac functionCell Metab. 2015;21:227–36.
Exercise is the archetype of physiologic demands placed on the cardiovascular system. Acute responses provide an informative assessment of cardiovascular function and fitness, while repeated exercise promotes cardiovascular health and evokes important molecular, structural, and functional changes contributing to its effects in primary and secondary prevention. Here we examine the use of exercise in murine models, both as a phenotypic assay and as a provocative intervention. We first review the advantages and limitations of exercise testing for assessing cardiac function, then highlight the cardiac structural and cellular changes elicited by chronic exercise and key molecular pathways that mediate these effects.

Poon C, Li RW, Seto SW, Kong SK, Ho HP, Hoi MP, et al.  In vitro vitamin K(2) and 1α,25‐dihydroxyvitamin D(3) combination enhances osteoblasts anabolism of diabetic miceEuropean Journal of Pharmacology.  2015;767:30–40.
Co-administration of vitamin K2 (10 nM) and 1,25(OH)2D3 (10 nM) caused an enhancement of calcium deposits in osteoblasts in both strains of mice. Vitamins K2 and 1,25(OH)2D3 co-administration time-dependently (7, 14 and 21 days) increased the levels of bone anabolic markers and bone formation transcription factors, with a greater magnitude of increase observed in osteoblasts of db/db mice. Combined vitamins K2 plus 1,25(OH)2D3 treatment significantly enhanced migration and the re-appearance of surface microvilli and ruffles of osteoblasts of db/db mice. Thus, our results illustrate that vitamins K2 plus D3 combination could be a novel therapeutic strategy in treating diabetes-associated osteoporosis.

Shea MK, Kritchevsky SB, Hsu F-C, Nevitt M, Booth SL, Kwoh CK, et al. The association between vitamin K status and knee osteoarthritis features in older adults: The Health, Aging and Body Composition Study. Osteoarthr Cart. 2015;23:370–378.
Vitamin K-dependent (VKD) proteins, including the mineralization inhibitor matrix-gla protein (MGP), are found in joint tissues including cartilage and bone. Previous studies suggest low vitamin K status is associated with higher osteoarthritis (OA) prevalence and incidence. To clarify what joint tissues vitamin K is relevant to in OA, we investigated the cross-sectional and longitudinal association between vitamin K status and knee OA structural features measured using magnetic resonance imaging (MRI). They found that community-dwelling men and women with very low plasma PK were more likely to have progression of articular cartilage and meniscus damage. Plasma (dp)ucMGP was associated with presence of knee OA features but not progression. Future studies are needed to clarify mechanisms underlying vitamin Ks role in OA.

Shao J, Wang Zhi,Yang T, Hing H, Zhang Y, Liu S.  Bone regulates glucose metabolism as an endocrine organ through osteocalcin.  Int J Endo.  2015;15:967673.
Skeleton was considered as a dynamic connective tissue, which was essential for mobility, calcium homeostasis, and hematopoietic niche. However, more and more evidences indicate that skeleton works not only as a structural scaffold but also as an endocrine organ, which regulates several metabolic processes. Besides osteoprotegerin (OPG), sclerostin (SOST), and Dickopf (DKK) which play essential roles in bone formation, modelling, remodelling, and homeostasis, bone can also secret hormones, such as osteocalcin (OCN), which promotes proliferation of β cells, insulin secretion, and insulin sensitivity. Additionally OCN can also regulate the fat cells and male gonad endocrine activity and be regulated by insulin and the neural system. In summary, skeleton has endocrine function via OCN and plays an important role in energy metabolism, especially in glucose metabolism.

Schnyder S, Handschin C.  Skeletal muscle as an endocrine organ:  PGC-1 α, myokines and exercise.  Bone.  2015 Nov;80:115-125.
An active lifestyle is crucial to maintain health into old age; inversely, sedentariness has been linked to an elevated risk for many chronic diseases. The discovery of myokines, hormones produced by skeletal muscle tissue, suggests the possibility that these might be molecular mediators of the whole body effects of exercise originating from contracting muscle fibers. In this review, we try to summarize the most recent developments in the study of muscle as an endocrine organ and speculate about the potential impact on our understanding of exercise and sedentary physiology, respectively. This article is part of a Special Issue entitled "Muscle Bone Interactions".

Torbergsen AC, Watne LO, Wyller TB, Frihagen F, Strømsøe K, Bøhmer T, et al.  Vitamin PK and 25(OH)D are independently and synergistically associated with a risk for hip fracture in an elderly population: A case control study. Clin Nutr. 2015;34:101–106.
The incidence of hipo fractures in Oslo is among the highest in the world.  Vitamin D, as well as vitamin K, may play an important role in bone metabolism.  We examined if vitamin K1 and 25(OH)D were associated with an increased risk of hip fracture, and whether the possible synergistic effect of these two micronutrients is mediated through bone turnover markers. We found that vitamin K1 and 25(OH)D are lower in hip fracture patients compared with controls. Vitamin K1 and 25(OH)D are independently and synergistically associated with the risk of hip fracture when adjusting for confounders. Intervention studies should include both vitamins.

Tsuka S, Aonuma F, Higashi S, Ohsumi T, Nagano K, Mizokami A, et al. Promotion of insulin-induced glucose uptake in C2C12 myotubes by osteocalcin. Biochem Biophys Res Commun. 2015;459:437–42.

Vainshtein A, Hood DA.  The regulation of autophagy during exercise in skeletal muscle.  J Applied Physio.  2015 Dec; https://doi.org/10.1152/japplphysiol.00550.2015
The merits of physical activity are numerous and well documented. However, the mechanisms underlying these robust adaptations are less clear and much sought after. Recently, an evolutionary conserved cellular recycling mechanism known as autophagy has been implicated in the adaptations to acute and chronic exercise. Autophagy is ever-ongoing in cells and tissues, ensuring cellular clearance and energy homeostasis. In this review we discuss recent developments in the field of autophagy and exercise. We specifically highlight the molecular mechanisms activated during acute exercise which lead to a prolonged adaptive response.

Vainshtein A, Tryon LD, Pauly M, Hood DA. Role of PGC-1alpha during acute exercise-induced autophagy and mitophagy in skeletal muscle. A J Physio Cell Physiol. 2015a;308 C710–C719. 
Regular exercise leads to systemic metabolic benefits, which require remodeling of energy resources in skeletal muscle. During acute exercise, the increase in energy demands initiate mitochondrial biogenesis, orchestrated by the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Much less is known about the degradation of mitochondria following exercise, although new evidence implicates a cellular recycling mechanism, autophagy/mitophagy, in exercise-induced adaptations. How mitophagy is activated and what role PGC-1α plays in this process during exercise have yet to be evaluated. Thus we investigated autophagy/mitophagy in muscle immediately following an acute bout of exercise or 90 min following exercise in wild-type (WT) and PGC-1α knockout (KO) animals. The results suggest that mitochondrial turnover is increased following exercise and that this effect is at least in part coordinated by PGC-1α.

Vossen LM, Schurgers, LJ, van Varik BJ, Kietselaer BL, Vermeer C, Meeder, JG, et all (2015). Menaquinone‐7 supplementation to reduce vascular calcification in patients with coronary artery disease: Rationale and study protocol (VitaK‐CAC Trial)Nutrients. 2015;7(11): 8905–8915.
Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial where we hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD.

Wang C, Qu B, Wang Z, Ju J, Wang Y, Wang Z, et al.  Proteomic identification of differentially expressed proteins in vascular wall of patients with ruptured intracranial aneurysms.  Atherosclerosis.  2015 Feb;238(2):201-6.

Andrukhova A, Streicher C, Zeitz U, Erben RH.  Fgf23 and parathyroid hormone signaling intact in kidney and bone.  Mol Cell Endrocinol.  2016 Nov;436:224-239.

Beaudart C, McCloskey E, Bruyère O, Cesari M, Rolland Y, Rizzoli R, et al.  Sarcopenia in daily practice:  assessment and management.  BMC Geriatr.  2016;16:170.
Sarcopenia is increasingly recognized as a correlate of ageing and is associated with increased likelihood of adverse outcomes including falls, fractures, frailty and mortality. Several tools have been recommended to assess muscle mass, muscle strength and physical performance in clinical trials. Whilst these tools have proven to be accurate and reliable in investigational settings, many are not easily applied to daily practice. This paper proposes some user-friendly and inexpensive methods that can be used to assess sarcopenia in real-life settings. Healthcare providers, particularly in primary care, should consider an assessment of sarcopenia in individuals at increased risk; suggested tools for assessing risk include the Red Flag Method, the SARC-F questionnaire, the SMI method or different prediction equations. Management of sarcopenia should primarily be patient centered and involve the combination of both resistance and endurance based activity programmes with or without dietary interventions.

Cabahug-Zuckerman P, Frikha-Benayed D, Majeska RJ, Tuthill A, Yakar S, Judex S, et al. Osteocyte apoptosis caused by hindlimb unloading is required to trigger osteocyte rankl production and subsequent resorption of cortical and trabecular bone in mice femurs. J Bone Miner Res. 2016;31:1356–1365.

Cartee GD, Hepple RT, Bamman MM, Zierath JR.  Exercise Promotes Healthy Aging of Skeletal Muscle. Cell Metab. 2016;23:1034–1047.
Primary aging is the progressive and inevitable process of bodily deterioration during adulthood. In skeletal muscle, primary aging causes defective mitochondrial energetics and reduced muscle mass. Secondary aging refers to additional deleterious structural and functional age-related changes caused by diseases and lifestyle factors. Secondary aging can exacerbate deficits in mitochondrial function and muscle mass, concomitant with the development of skeletal muscle insulin resistance. Exercise opposes deleterious effects of secondary aging by preventing the decline in mitochondrial respiration, mitigating aging-related loss of muscle mass and enhancing insulin sensitivity. This review focuses on mechanisms by which exercise promotes "healthy aging" by inducing modifications in skeletal muscle.

El-Brashy AEWS, El-Tanawy RM, Hassan WA, Shaban HM, Bhnasawy MM. Potential role of vitamin K in radiological progression of early knee osteoarthritis patients. Egypt. Rheumatol. 2016;38:217–223.
Vitamin K is necessary for the functional activation of vitamin K dependent proteins via gamma-carboxylation process. These proteins are present in bone and cartilage beside their participation in coagulation cascade. This study aimed to assess plasma vitamin K1(phylloquinone) concentrations in primary early osteoarthritis (KOA) patients and to correlate these levels with clinical parameters and radiological progression using plain radiography and musculoskeletal ultrasound (MSUS). The results showed that knee osteoarthritis patients have significantly decreased plasma levels of vitamin K that was remarkably associated with radiological progression of early disease suggesting that it could be a useful marker to reflect OA severity and implies a possible role in the disease pathogenesis.

Finnes TE, Lofthus CM, Meyer HE, Søgaard AJ, Tell, GS, Apalset EM, et al.   A combination of low serum concentrations of vitamins PK and D is associated with increased risk of hip fractures in elderly Norwegians: A NOREPOS study. Osteoporos. Int. 2016;27:1645–1652.
The present study investigated the risk of incident hip fractures according to serum concentrations of vitamin K1 and 25-hydroxyvitamin D in elderly Norwegians during long-term follow-up. The results showed that the combination of low concentrations of both vitamin D and K1 provides a significant risk factor for hip fractures.

Fusaro M, Gallieni M, Rizzo MA, Stucchi A, Delanaye P, Cavalier, et al.  Vitamin K plasma levels determination in human health.  Clin Chem Lab Med.  2016;55(6):789-799.

Greenhill C.  Osteocalcin in the adaptation to exercise.  Nature Reviews Endocrinology.  2016;12:434.

Harshman SG, Shea MK.  The role of vitamin K in chronic aging diseases;  Inflammation, cardiovascular disease, and osteoarthritis.  Curr Nutr Rep.  2016 Jun;5(2):90-98.
Vitamin K is an enzyme cofactor required for the carboxylation of vitamin K dependent proteins, several of which have been implicated in diseases of aging. Inflammation is recognized as a crucial component of many chronic aging diseases and evidence suggests vitamin K has an anti-inflammatory action that is independent of its role as an enzyme co-factor. Vitamin K-dependent proteins and inflammation have been implicated in cardiovascular disease and osteoarthritis, which are leading causes of disability and mortality in older adults. The purpose of this review is to summarize observational studies and randomized trials focused on vitamin K status and inflammation, cardiovascular disease, and osteoarthritis.

Hawellek T, Hubert J, Hischke S, Krause M, Bertrand J, Pap T., Püschel K, et al. Articular cartilage calcification of the hip and knee is highly prevalent, independent of age but associated with histological osteoarthritis: Evidence for a systemic disorder. Osteoarthr. Cartil. 2016;24:2092–2099.

Jiang X, Tao H, Qiu C, Ma X, Li, S, Guo, X, Lv A, et al.  Vitamin K2 regression aortic calcification induced by warfarin via Gas6/Axl survival pathway in ratsEuropean Journal of Pharmacology. 2016;786:10–18.
The aim of this study was to investigate the effect of vitamin K2 on aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats. A calcification model was established by administering 3mg/g warfarin to rats. 100μg/g vitamin K2 reversed 44% calcification. In conclusion, we established a warfarin-induced calcification model and showed vitamin K2 can inhibit warfarin-induced aortic calcification and apoptosis. The regression of aortic calcification by vitamin K2 involved the Gas6/Axl axis. This data may provide a theoretical basis for future clinical treatments for aortic calcification.

Joseph AM, Adhihetty PJ, Leeuwenburgh C. Beneficial effects of exercise on age-related mitochondrial dysfunction and oxidative stress in skeletal muscle. J Physiol. 2016;594:5105–5123.
Mitochondria are negatively affected by ageing leading to their inability to adapt to higher levels of oxidative stress and this ultimately contributes to the systemic loss of muscle mass and function termed sarcopenia. Since mitochondria are central mediators of muscle health, they have become highly sought‐after targets of physiological and pharmacological interventions. Exercise is the only known strategy to combat sarcopenia and this is largely mediated through improvements in mitochondrial plasticity. When mitochondrial quality is compromised and homeostasis is not re‐established, myonuclear cell death is activated and muscle atrophy ensues. In contrast, acute and chronic exercise attenuates these deficits, restoring mitochondrial turnover and promoting a healthier mitochondrial pool that leads to the preservation of muscle. Based on these observations, understanding how advancing age and exercise influence mitochondria in older muscle will provide invaluable insight into the development of exercise protocols that will maximize beneficial adaptations in the elderly. 

Ju J-s, Jeon S-II, Park J-Y. Autophagy plays a role in skeletal muscle mitochondrial biogenesis in an endurance exercise-trained condition.  J Physio Sci.  2016 Mar:66(5):417-430.
Mitochondrial homeostasis is tightly regulated by two major processes: mitochondrial biogenesis and mitochondrial degradation by autophagy (mitophagy). Research in mitochondrial biogenesis in skeletal muscle in response to endurance exercise training has been well established, while the mechanisms regulating mitophagy and the interplay between mitochondrial biogenesis and degradation following endurance exercise training are not yet well defined. This study examined the effects of a short-term inhibition of autophagy in response to acute endurance exercise on skeletal muscle mitochondrial biogenesis and dynamics in an exercise-trained condition. The results suggest that autophagy plays an important role in mitochondrial biogenesis and this coordination between these opposing processes is involved in the cellular adaptation to endurance exercise training.

Karsenty G, Olsen EN.  Bone and muscle endocrine functions:  unexpected paradigms of inter-organ communication.  2016 Mar;165(6):1248-56.
Most physiological functions originate with the communication between organs. Mouse genetics has revived this holistic view of physiology through the identification of inter-organ communications that are unanticipated, functionally important and would have been difficult to uncover otherwise. This review highlights this point by showing how two tissues usually not seen as endocrine ones, bone and striated muscles, influence in a significant manner several physiological processes.

Kim SJ, Ahn J, Kim HK, Kim JH.  Obese children experience more extremity fractures than nonobese children and are significantly more likely to die from traumatic injuries.  Acta Paediatr.  2016 Oct;105(10):1152-1157.
Two of the most prevalent problems children facing worldwide are injuries and obesity. We conducted a systematic review of published studies that evaluated the effects of obesity on children with traumatic injuries. Obese children were 25% more likely to have extremity fractures than nonobese children (p = 0.003), and their mortality rate was significantly higher at 4.7% versus 2.8% (p = 0.026). Our review showed that obese children were more likely to have extremity fractures and die of traumatic injuries than nonobese children.

Kristensen JH, Karsdal MA.  Chapter 30, Elastin in Biochemistry of Collagens, Laminins and Elastin.  2016, pages 197-201.
Elastin is a key extracellular matrix (ECM) protein that provides resilience and elasticity to tissues and organs. Elastin is roughly 1000 times more flexible than collagens; thus, the main function of elastin is the elasticity of tissues. It is the dominant protein in extensible tissues and is primarily present in the lungs, aorta, and skin. Mutations in the elastin gene may lead to diseases such as Williams–Beuren syndrome, cutis laxa, and supravalvular aortic stenosis (SVAS). The precursor of elastin is tropoelastin. Tropoelastin is derived from fibroblasts, smooth muscle cells, chondrocytes, or endothelial cells before it is processed to elastin by cleavage of its signal peptide. Elastin monomers are crosslinked during the formation of desmosine molecules. Several important and well-described biomarkers of elastin degradation are available.

Lazarus NR, Harridge SDR.  Declining performance of master athletes:  silhouettes of the trajectory of healthy human ageing?  J of Physio.  2016;595(9):2941-2948.
Analysis of world record performances by master athletes suggests an essentially linear decline with age until around the eighth decade after which performance decline accelerates. Because these records are obtained from highly trained individuals they can be viewed as being reflective of the diminution of integrative physiological prowess that occurs solely as a result of ageing, unaffected by the confounding effects of inactivity. It can also be argued that these performance profiles mirror and provide an insight into the trajectory of the physiology of the human ageing process. Here we propose a set point theory that hypothesizes that a given threshold of physical activity is needed to age optimally and to maximize the ‘healthspan’. Exercising at levels below the set point will result in ageing being contaminated by the unpredictable and pathological effects of inactivity. Exercise above this threshold stimulates adaptations towards maximising athletic performance, but is unlikely to have further beneficial effects on health. Thus the decades-long, controlled diminution in athletic performance, should not be seen as a disease process. The ageing process is separate from, and independent of, exercise-mediated processes that maintain or adapt physiological function. However, any model which does not take into account the effects of activity will not adequately describe the inherent ageing process.

Levinger I, Lin X,  Zhang X, Brennan-speranza TC, Volpato B, Hayes A, et al.  The effects of muscle contraction and recombinant osteocalcin on insulin sensitivity ex vivo.  Osteoporos Int.  2016 Feb;27(2):653-63.
Acute exercise increases skeletal muscle insulin sensitivity. In humans, exercise increases circulating ucOC, a hormone that increases insulin sensitivity in rodents. We tested whether GPRC6A, the putative receptor of ucOC, is present in mouse muscle and whether recombinant ucOC increases insulin sensitivity in both C2C12 myotubes and whole mouse muscle following ex vivo muscle contraction. This study found that GPRC6A, the likely receptor of osteocalcin (OC), is expressed in mouse muscle. ucOC treatment augments insulin-stimulated skeletal muscle glucose uptake in C2C12 myotubes and following ex vivo muscle contraction. ucOC may partly account for the insulin sensitizing effect of exercise.

Lin X, Hanson E, Betik Ac, Brennan-speranza TC, Hayes A, Levinger I.  Hindlimb immobilization, but not castration, induces reduction of undercarboxylated osteocalcin associated with muscle atrophy in rats.  J Bone Miner Res.  2016 Nov;31(11):1967-1978.
Undercarboxylated osteocalcin (ucOC) has been implicated in skeletal muscle insulin sensitivity and function. However, whether muscle mass and strength loss in atrophic conditions is related to a reduction in ucOC is not clear. We hypothesized that both immobilization and testosterone depletion would lead to reductions in ucOC, associated with not only the degree of muscle atrophy but also changes to atrophy signaling pathway(s) in male rats. We subjected 8-week-old male Fischer (F344) rats to 7 days of hindlimb immobilization 10 days after castration surgery. Hindlimb immobilization, but not castration, resulted in a significant reduction in ucOC (30%) and lower ucOC was correlated with the degree of muscle loss and muscle weakness. These data suggest that ucOC may have other effects on skeletal muscle in addition to its insulin sensitizing effect.

Mera P, Laue K, Wei J, Berger JM, Karsenty G. Osteocalcin is necessary and sufficient to maintain muscle mass in older miceMol Metab. 2016;5:1042–7. 
A decrease in muscle protein turnover and therefore in muscle mass is a hallmark of aging. Because the circulating levels of the bone-derived hormone osteocalcin decline steeply during aging in mice, monkeys and humans we asked here whether this hormone might regulate muscle mass as mice age. They examined muscle mass and strength in mice lacking osteocalcin (Ocn-/-) or its receptor in all cells (Gprc6a-/-) or specifically in myofibers (Gprc6a Mck -/-) as well as in 9 month-old WT mice receiving exogenous osteocalcin for 28 days. They found that osteocalcin signaling in myofibers is necessary to maintain muscle mass in older mice in part because it promotes protein synthesis in myotubes without affecting protein breakdown. We further show that treatment with exogenous osteocalcin for 28 days is sufficient to increase muscle mass of 9-month-old WT mice.  This study uncovers that osteocalcin is necessary and sufficient to prevent age-related muscle loss in mice.

Mera P, Laue K, Ferron M, Confavreux C, Wei J, Galán-Díez M, et al. Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exerciseCell Metab. 2016;23:1078–92. 
Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time those of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15 month-old mice the exercise capacity of 3 month-old mice. This study uncovers a bone to muscle feed-forward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.

Pernas L, Scorrano L. Mito-Morphosis: Mitochondrial Fusion, Fission, and Cristae Remodeling as Key Mediators of Cellular Function. Annu Rev Physiol. 2016;78:505-31.

Pi M, Kapoor K, Ye R, Nishimoto SK, Smith JC, Baudry J.  Evidence for osteocalcin binding and activation of GPRC6A in β-cells. Endocrinology, 2016;157(5):1866-1880.
The possibility that G protein-coupled receptor family C member A (GPRC6A) is the osteocalcin (Ocn)-sensing G protein-coupled receptor that directly regulates pancreatic β-cell functions is controversial. In the current study, we found that Ocn and an Ocn-derived C-terminal hexapeptide directly activate GPRC6A-dependent ERK signaling in vitro. The data from computational modeling establish the structural basis for Ocn direct activation of GPRC6A and confirm a role for GPRC6A in regulating β-cell proliferation and insulin secretion.

Rønn S, Harsløf T, Pedersen S, Langdahl B. Vitamin K2 (menaquinone-7) prevents age-related deterioration of trabecular bone microarchitecture at the tibia in postmenopausal women. Eur. J. Endocrinol. 2016;175:541–549.
Clinical studies suggest that vitamin K2 protects against bone loss and fractures; however, its effect on bone quality has never been investigated. We investigated the effect of vitamin MK-7 on undercarboxylated osteocalcin (ucOC), and bone mass and quality. We investigated the effect of MK-7 375 µg for 12 months on bone mineral density (BMD), bone microarchitecture, and  biochemical bone turnover markers in 148 postmenopausal women with osteopenia. All of them were supplemented with calcium and vitamin D.  The data showed that MK7 preserves trabecular bone structure at the tibia.   They found that older adults with higher vitamin status had better physical performance scores at baseline.  Future studies are needed to determine if vitamin K supplementation could improve function in those with vitamin K insufficiency and clarify the underlying mechanism.

Shea MK, Loeser RF, Hsu FC, et al. Vitamin K status and lower extremity function in older adults: the health aging and body composition study. J Gerontol A Biol Sci Med Sci2016;71:1348–1355.
While low vitamin K status has been associated with several chronic diseases that can lead to lower extremity disability, it is not known if low vitamin K status is associated with worse lower extremity function.  Vitamin K status was measured according to plasma phylloquinone (vitamin K1) and dephosphorylated-uncarboxylated MGP (dp-ucMGP) in 1,089 community-dwelling older adults (mean ± SD age =74±3 years; 67% female). Lower extremity function was assessed using the short physical performance battery (SPPB), gait speed, and isokinetic leg strength. Older adults with higher vitamin K status had better physical performance scores at baseline.  Since lower extremity disability is a common consequence of multiple chronic diseases for which a role of vitamin K has been suggested, future studies are needed to determine if vitamin K supplementation could improve function in those with vitamin K insufficiency and clarify underlying mechanism(s).

van der Zwaard S, de Ruiter CJ, Noordhof DA, Sterrenburg R, Bloemers FW, de Koning JJ, et alMaximal oxygen uptake is proportional to muscle fiber oxidative capacity, from chronic heart failure patients to professional cyclistsJ Appl Physiol (1985).  2016 Sep;121: 636–645. 
V̇o2 max during whole body exercise is presumably constrained by oxygen delivery to mitochondria rather than by mitochondria's ability to consume oxygen. Humans and animals have been reported to exploit only 60-80% of their mitochondrial oxidative capacity at maximal oxygen uptake (V̇o2 max). We determined to what extent V̇o2 max attained during cycling exercise differs from mitochondrial oxidative capacity predicted from SDH activity of vastus lateralis muscle in chronic heart failure patients, healthy controls, and cyclists. V̇o2 max was assessed in 20 healthy subjects and 28 cyclists, and SDH activity was determined from biopsy cryosections of vastus lateralis using quantitative histochemistry. We conclude that human V̇o2 max is related to mitochondrial oxidative capacity predicted from skeletal muscle SDH activity. Mitochondrial oxidative capacity is likely marginally limited by oxygen supply to mitochondria.

Weaver CM, Gordon CM, Janz KF, Kalkwarf HJ, Lappe JM, Lewis R, et al. The national osteoporosis foundation's position statement on peak bone mass development and lifestyle factors: A systematic review and implementation recommendations. Osteoporos Int 2016;27:1281-386.
Lifestyle choices influence 20–40 % of adult peak bone mass. Therefore, optimization of lifestyle factors known to influence peak bone mass and strength is an important strategy aimed at reducing risk of osteoporosis or low bone mass later in life. This current review is a systematic update of the previous review conducted by the National Osteoporosis Foundation.

Wei F‐F , Drummen NEA, Schutte AE, Thijs L , Jacobs L , Petit T ,et al. Vitamin K dependent protection of renal function in multi‐ethnic population studieseBioMedicine.  2016;4:162–169.
Following activation by vitamin K (VK), matrix Gla protein (MGP) inhibits arterial calcification, but its role in preserving renal function remains unknown. In 1166 white Flemish (mean age, 38.2 years) and 714 South Africans (49.2% black; 40.6 years), we correlated estimated glomerular filtration (eGFR [CKD-EPI formula]) and stage of chronic kidney disease (CKD [KDOQI stages 2-3]) with inactive desphospho-uncarboxylated MGP (dp-ucMGP), using multivariable linear and logistic regression.  They found that eGFR decreases and CKD risk increases with higher dp-ucMGP, a marker of VK deficiency. These findings highlight the possibility that VK supplementation might promote renal health.

Yu Y, Li Y, Gao F, Hu Q, Zhang Y, Chen D, Wang G. Vitamin K2 suppresses rotenone-induced microglial activation in vitro. Acta Pharmacol Sin. 2016;37:1178–1189.
Increasing evidence has shown that environmental factors such as rotenone and paraquat induce neuroinflammation, which contributes to the pathogenesis of Parkinson's disease (PD). In this study, we investigated the molecular mechanisms underlying the repression by menaquinone-4 (MK-4), a subtype of vitamin K2, of rotenone-induced microglial activation in vitro. MK-4 (5-20 μmol/L) restored the mitochondrial membrane potential that had been damaged by rotenone. However, this rotenone-activated microglia-mediated death of SH-SY5Y cells was significantly attenuated when the BV2 cells were co-treated with MK-4 (5-20 μmol/L). Vitamin K2 can directly suppress rotenone-induced activation of microglial BV2 cells in vitro by repressing ROS production and p38 activation.

Zampieri S, Mammucari C, Romanello V, Barberi L, Pietrangelo L, Fusella A, et al.  Physical exercise in aging human skeletal muscle increases mitochondrial calcium uniporter expression levels and affects mitochondria dynamics.  Physiol Rep.  2016 Dec;4(24):e13005.

Bayramoğlu M, Ünlütürk, N.  Nonhealing, progressive stress fractures of the foot in a 13-year-old basketball player:  is vitamin K deficiency a risk factor?  J Phys Ther Sci.  2017 Apr;29(4):763-766.
This study writes up a case of an adolescent male basketball player with nonhealing stress fractures of the foot and discuss the probable factors. A 13-year-old basketball player presented with right foot pain. He had been playing basketball for three years and practicing 5 days/week. He denied any increase in daily training intensity. Magnetic resonance imaging confirmed stress fractures of the cuboid and cuneiform, with mild edema of the soft tissues between the tarsal bones and tenosynovitis of the flexor hallucis and flexor digitorum longi. The foot was immobilized for 4 weeks, with progressive weight bearing introduced at the fifth week. At the 6th week, while still restricted to partial weight bearing, he reported diffuse severe pain. The entire foot was painful with palpation, and new imaging showed stress fractures of the talus, cuboid, cuneiform, and proximal first metatarsal bones, and tenosynovitis of the flexor hallucis longus and flexor digitorum longus tendons with progression of the soft tissue edema around the tarsal bones. Acute phase reactants were elevated; vitamin K level was low. He started participating in games again at the 6th month post-injury. Management of patients with stress fractures includes immobilization, physical therapy, and biomechanical arrangements. If the expected healing does not occur, a deficiency of vitamin K might be considered as a factor. Questioning on dietary habits of the patient and encouraging adequate intake of the deficient nutrient might assist in the healing process. Key words: Stress fractures, Vitamin K

Cai X, Xing J, Long CL, Peng Q,  Humphrey MB. DOK3 modulates bone remodeling by negatively regulating osteoclastogenesis and positively regulating osteoblastogenesis. J Bone Min Res. 2017;32:2207–2218

Che L, Li D. The effects of exercise on cardiovascular biomarkers: new Insights, recent data, and applicationsAdv Exp Med Biol. 2017;999:43–53.
The benefit of regular exercise or physical activity with appropriate intensity on improving cardiopulmonary function and endurance has long been accepted with less controversy. The challenge remains, however, quantitatively evaluate the effect of exercise on cardiovascular health due in part to the amount and intensity of exercise varies widely plus lack of effective, robust and efficient biomarker evaluation systems. In this review, we systemic reviewed the latest novel biomarkers in metabolomics, genomics, proteomics, and molecular imaging mainly focus on heart health, as well as cardiovascular diseases such as atherosclerosis and ischemic heart disease. Finally, we discuss the clinical relevance of physical activity and exercise on key biomarkers in molecular basis and practical considerations.

Dantoft TM, Ebstrup JF, Linneberg A, Skovbjerg S, Madsen AL, Mehlsen J, et al.  Cohort description: the Danish Study of Functional Disorders.  Clin Epidemio. 2017 Feb 23;9:127-139.

Dipla K, Triantafyllou A, Loketsos N, Papadopoulos S, Sachpekidis V, Vrabas IS, et al.  Impaired muscle oxygenation and elevated exercise blood pressure in hypertensive patients:  links with vascular stiffness.  Hypertension.  2017 Aug;70(2):444-451.
This study examined in vivo (1) skeletal muscle oxygenation and microvascular function, at rest and during handgrip exercise, and (2) their association with macrovascular function and exercise blood pressure (BP), in newly diagnosed, never-treated patients with hypertension and normotensive individuals. Ninety-one individuals (51 hypertensives and 40 normotensives) underwent office and 24-hour ambulatory BP, arterial stiffness, and central aortic BP assessment, followed by a 5-minute arterial occlusion and a 3-minute submaximal handgrip exercise. In conclusion, nontreated patients with hypertension exhibit prominent reductions in in vivo indices of skeletal muscle oxidative capacity, suggestive of mitochondrial dysfunction, and blunted muscle microvascular reactivity. These dysfunctions were associated with higher aortic systolic BP and arterial stiffness. Dysregulations in muscle oxygen delivery/utilization and microvascular stiffness, in hypertensive patients, partially contribute to their exaggerated BP during exercise.

Fusaro M, Mereu MC, Aghi A, Iervasi G, Gallieni M.  Vitamin K and bone.  Clin Cases Miner Bone Metab.  2017 May-Aug;14(2):200-206.
Vitamin K is mainly known as an agent involved in blood coagulation, maintaining the activity of coagulation factors in the liver. In addition, epidemiological studies suggested that a lack of vitamin K is associated with several diseases, including osteoporosis and vascular calcification. There are two main kinds of vitamin K: Phylloquinone (or PK) and Menaquinones (MKn), both act as co-enzyme of y-glutamyl carboxylase (GGCX) transforming under-carboxylated in carboxylated vitamin K dependent proteins, such as Bone Gla Protein (or Osteocalcin) and Matrix Gla Protein. Recently, Vitamin K was also identified as a ligand of the nuclear steroid and xenobiotic receptor (SXR) (in murine species Pregnane X Receptor: PXR), expressed in osteoblasts. The purpose of this literature review is to evaluate the protective role of Vitamin K in bone and vascular health.

Glancy B, Hartnell LM, Combs CA, et al.  Power grid protection of the muscle mitochondrial reticulum.  Cell Reports.  2017;19(3):487-496.
Mitochondrial network connectivity enables rapid communication and distribution of potential energy throughout the cell. However, this connectivity puts the energy conversion system at risk since damaged elements could jeopardize the entire network. Here we demonstrate the mechanisms for mitochondrial network protection in heart and skeletal muscle (SKM). We find that the cardiac mitochondrial reticulum is segmented into subnetworks comprised of many mitochondria linked through abundant contact sites at highly specific intermitochondrial junctions (IMJs). Regional mitochondrial subnetworks limit the cellular impact of local dysfunction while the dynamic disconnection of damaged mitochondria allows the remaining mitochondria to resume normal function within seconds.

Gordeladze JO.  Vitamin K2.  In Vitamin K2 - Vital for Health and Wellbeing. InTech,Mar 2017. URL: https://doi.org/10.5772/66384, doi:10.5772/66384.
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner a...

Granata C, Oliveira RSF, Little JP, Renner K, Bishop DJ.  Sprint-interval but not continuous exercise increases PGC-1a content and 53 phosphorylation in nuclear fractions of human skeletal muscle.  Scientific Reports.  2017;7:44227.
Our findings indicate that “all-out” SIE represents a valuable and possibly superior option to moderate-intensity CE for promoting the early molecular events leading to exercise-induced mitochondrial biogenesis, in a time-efficient manner.

Greggio C, Jha P, Kulkarni SS, Lagarrigue S, Broskey NT, Boutant M, Wang X, et al.  Enhanced respiratory chain supercomplex formation in response to exercise in human skeletal muscle.  Cell Metab.  2017 Feb 7;25(2):301-311.
Mitochondrial dysfunction is a hallmark of multiple metabolic complications. Physical activity is known to increase mitochondrial content in skeletal muscle, counteracting age-related decline in muscle function and protecting against metabolic and cardiovascular complications. Here, we investigated the effect of 4 months of exercise training on skeletal muscle mitochondria electron transport chain complexes and supercomplexes in 26 healthy, sedentary older adults. Exercise differentially modulated respiratory complexes. Overall, supercomplex content was increased after exercise. Taken together, our results provide the first evidence that exercise affects the stoichiometry of supercomplex formation in humans and thus reveal a novel adaptive mechanism for increased energy demand.

Harper J, O’Donnell E, Sorouri Khorashad B, et al.  How does hormone transition in transgender women change body composition, muscle strength and haemoglobin? Systemic review with a focus on the implications for sport participation.  British Journal of Sports Med.  2021;55:865-872.

Hao G, Zhang B, Gu M, et al. Vitamin K intake and the risk of fractures: a meta-analysis. Medicine (Baltimore)2017;96(17);e6725.
This study performed a meta-analysis of cohort or nested case-control studies to investigate the relationship between dietary vitamin K intake and the risk of fractures. A comprehensive search of PubMed and EMBASE (to July 11, 2016) was performed to identify cohort or nested case-control studies providing quantitative estimates between dietary vitamin K intake and the risk of fractures. Our study suggests that higher dietary vitamin K intake may moderately decrease the risk of fractures.

Janssen R, Vermeer C.  Vitamin K deficit and elastolysis theory in pulmonary elasto-degenerative diseases.  Medical Hypotheses.  2017 Oct;108:38-41.
Elastin is a unique protein providing deformability and resilience to dynamic tissues, such as arteries and lungs. It is an absolute basic requirement for circulation and respiration. Elastin can be degraded by elastases and has a high calcium affinity. Elastin calcification and elastin degradation are two pathological processes that impair elastin’s functioning. Furthermore, elastin degradation can be associated to elastin calcification. Matrix Gla Protein (MGP) is probably the most potent natural inhibitor of elastin calcification and requires vitamin K for its activation. Dp-ucMGP reflects the burden of vitamin K-dependent proteins that have not been activated by vitamin K and could therefore best be regarded as a biomarker of a vitamin K deficit. Dp-ucMGP levels decrease after vitamin K supplementation.Recently, we discovered a strong correlation between plasma dp-ucMGP and plasma DES levels in both patients with chronic obstructive pulmonary disease (COPD) and controls. The ‘Vitamin K deficit and elastolysis theory’ posits that elastin degradation causes a rise in the vitamin K deficit and implies that vitamin K supplementation could be preventing elastin degradation. If this hypothesis holds true and is universally found in every state and condition, it will have an unprecedented impact on the management of every single pulmonary disease characterized by accelerated elastin degradation, such as alpha-1 antitrypsin deficiency, bronchiectsas, COPD and cystic fibrosis. Theoretically, a plasma dp-ucMGP concentration of zero would be associated with a near-complete standstill of elastin degradation and disease progression in patients  with any of these debilitating conditions.

Ju J-s.  Regulation of mitochondrial homeostasis in response to endurance exercise training in skeletal muscle.  J Life Sci.  2017;27(3):361-369.
Mitochondrial homeostasis is tightly regulated by two major processes: mitochondrial biogenesis and mitochondrial degradation by autophagy (mitophagy). Research in mitochondrial biogenesis in skeletal muscle in response to endurance exercise training has been well established, while the mechanisms regulating mitophagy and the relationship between mitochondrial biogenesis and degradation following endurance exercise training are not yet well defined. In this review paper, the molecular mechanisms regulating mitochondrial biogenesis and mitophagy and the coordination between the opposing processes is involved in the cellular adaptation to endurance exercise training in skeletal muscle will be discussed.

Karsenty G.  Update on the biology of osteocalcin.  Endocrine Practice.  2017 Oct;23(10):1270-1274.
A genetics approach has uncovered that bone has more functions than expected. Bone is an endocrine organ that secretes a growing number of hormones. In that context, the discovery of the osteoblast-derived hormone osteocalcin has significantly broadened the field of bone biology because of the number of physiologic processes regulated by this hormone. At present, osteocalcin has been shown to enhance several aspects of energy metabolism, brain development, and cognition. These discoveries shed light on the cross-talk between multiple organs and provide credence to the search for additional endocrine functions of bone.

Laughlin MH, Yang HT, Tharp DL, Rector RS, Padilla J, Bowles DK. Vascular cell transcriptomic changes to exercise training differ directionally along and between skeletal muscle arteriolar treesMicrocirculation.  2017;24:e12336.

Lin X, Parker L, McLennan E, Zhang X, Hayes A, McConell G, et al. Recombinant uncarboxylated osteocalcin per se enhances mouse skeletal muscle glucose uptake in both extensor digitorum longus and soleus muscles.  Front Endocrinol.  2017;8:330.
Emerging evidence suggests that undercarboxylated osteocalcin (ucOC) improves muscle glucose uptake in rodents. Our study suggests that, since ucOC increases muscle glucose uptake without insulin, it could be considered as a potential agent to improve muscle glucose uptake in insulin resistant conditions.

Ireland A, Rittweger J. Exercise for osteoporosis: how to navigate between overeagerness and defeatism. J Musculoskelet Neuronal Interact. 2017;17(3):155–161.
Osteoporosis and associated fractures remain a common and costly health problem. Public fears about rare side effects of efficacious drug treatments for osteoporosis have contributed to decreased prescription and compliance. Exercise and physical activity-based interventions have long been proposed as an alternative treatment for osteoporosis. In this perspective, we summarize the available evidence in support of exercise on bone mass. They highlight the successful application of exercise to attenuating or even partially reversing bone loss in musculoskeletal disuse. We then propose how collaboration between basic science and clinical partners, and consideration of factors such as exercise modality, exercise intensity and participation motivation could improve exercise efficacy.

Karpinski M, Popko J, Maresz K, Badmaev V, Stohs SJ.  Roles of vitamins D and K, nutrition, and lifestyle in low-energy bone fractures in children and young adults.  J of Am College of Nutrition.  2017;36(4):399-412.
This review focuses on the role of vitamin K in combination with vitamin D and other factors in bone health. The current understanding is that maintaining bone health and prevention of low-energy fractures in any pediatric population includes nutritional factors combined with an active lifestyle. The beneficial role of vitamin K, particularly vitamin K2 as menaquinone-7 (MK-7), in bone and cardiovascular health is well supported scientifically.  Osteocalcin and matrix-Gla (glutamate-containing) protein (MGP) exemplify vitamin K–dependent proteins involved in building bone matrix and keeping calcium from accumulating in the arterial walls, respectively. An important part of the mechanism of vitamin K involves carboxylation and posttranslational activation of the family of vitamin K–dependent proteins, which prevent expression of pro-inflammatory factors and support improvement in bone mineral concentration, bone mineral density, and the quality of bone matrix. Understanding the combined approach to a healthy skeletal system in children and young adults, including the roles of vitamins D and K, calcium, healthy diet, and exercise, is particularly important in view of reports of subclinical insufficiency of vitamins D and K in otherwise healthy pediatric populations with low-energy bone fractures.

Kundi R, Prior SJ, Addison O, Lu M, Ryan AS, Lal BK.  Contrast-enhanced ultrasound reveals exercise-induced perfusion deficits in claudicants.  J Vasc Endovasc Surg.  2017;2(1):9.
Thirteen patients with Rutherford Class I-III Peripheral Arterial Disease (PAD) and no prior revascularization procedures were recruited from the Baltimore Veterans Affairs Medical Center and compared with eight control patients without PAD. CEUS interrogation of the index limb gastrocnemius muscle was performed using an intravenous bolus of lipid-stabilized microsphere contrast before and after a standardized treadmill protocol. Peak perfusion (PEAK) and time to peak perfusion (TTP) were measured before and after exercise. Consistent with their lack of ischemic symptoms at rest, PAD patients showed similar perfusion measures (TTP and PEAK) at rest. PAD patients, however, were unable to increase perfusion in response to exercise, whereas controls increased perfusion significantly. This corresponds with claudication and limited walking capacity observed in PAD.

Laker RC. Drake JC, Wilson RJ, Lira VA, Lewellen BM, Ryall KA. et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat Commun. 2017;8:548. 

Lecka-Czernik, B. Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia.  2017;60:1163–1169.

Levinger I, Brennan-Speranza TC, Zulli A, Parker L, Lin X, Lewis JR, et al., Multifaceted interaction of bone, muscle, lifestyle interventions and 363 metabolic and cardiovascular disease: role of osteocalcin. Osteoporos Int. 2017;28(8):2265-2273.
Undercarboxylated osteocalcin (ucOC) may play a role in glucose homeostasis and cardiometabolic health. This review examines the epidemiological and interventional evidence associating osteocalcin (OC) and ucOC with metabolic risk and cardiovascular disease. Current observational and indirect interventional evidence appears to support a relationship between ucOC with metabolic and cardiovascular disease. There is also emerging evidence to suggest a direct role of ucOC in human metabolism.

Lu W-C, Pringa E, Chou L. Effect of magnesium on the osteogenesis of normal human osteoblasts. Magnes Res. 2017;30:42–52.
The present study based on an experimental design demonstrated the impact of 2 mM supplemented Mg2+ on induced-proliferation and differentiation of normal human osteoblasts.

Marles RJ, Roe AL, Oketch-Rabah HA.  US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K.  Nutrition Reviews.  2017 Jul;75(7). 553-578.
Vitamin K plays important biological roles in maintaining normal blood coagulation, bone mineralization, soft tissue physiology, and neurological development. Menaquinone-7 is a form of vitamin K2 that occurs naturally in some animal-derived and fermented foods. It is also available as an ingredient of dietary supplements. Menaquinone-7 has greater bioavailability than other forms of vitamin K, which has led to increasing sales and use of menaquinone-7 supplements. This special article reviews the chemistry, nomenclature, dietary sources, intake levels, and pharmacokinetics of menaquinones, along with the nonclinical toxicity data available and the data on clinical outcomes related to safety (adverse events). In conclusion, the data reviewed indicate that menaquinone-7, when ingested as a dietary supplement, is not associated with any serious risk to health or with other public health concerns..

McFarlin BK, Henning AL, Venable AS.  Oral consumption of Vitamin K2 for 8 weeks associated with increased maximal cardiac output during exercise.  Altern Ther Health Med.  2017 Jul;23(4):26-32.
Vitamin K1 and K2 are not typically common in a Western diet because they are found in a variety of fermented foods. Vitamin K2 in particular has been demonstrated to restore mitochondrial function and has a key role in production of mitochondrial adenosine triphosphate. Thus, it is reasonable to speculate that dietary supplementation with vitamin K2 could increase the function of muscle with high mitochondrial content (ie, skeletal and cardiac muscle.  The purpose of this study was to determine if 8 wk of dietary supplementation with Vitamin K2 could alter cardiovascular responses to a graded cycle ergometer test. The study was a randomized controlled trial study that took place in the Applied Physiology Laboratory of the Department of Biological Sciences at the University of North Texas (Denton, TX, USA). Participants were aerobically trained males and female athletes (N = 26). Participants were randomly assigned either to a control group that received a rice flour placebo or to an intervention group that received vitamin K2. For weeks 1 to 4, participants received 300 mg/d; for weeks 5 to 8, they received 150 mg/d. Subjects assigned to the control group received similar doses to mirror the intervention group. Subjects consumed the supplements during an 8-wk period while they maintained their typical exercise habits. At baseline and postintervention, participants completed a standard, graded exercise test on an electronically braked cycle ergometer. Before the test, participants were fitted with a mouth piece, and their oxygen consumption, carbon dioxide production, respiratory rate, and respiratory exchange ratio were measured. In addition, participants were fitted with skin-mounted electrodes that measured noninvasive cardiac output, stroke volume, and heart rate. Vitamin K2 supplementation was associated with a 12% increase in maximal cardiac output, with P = .031, with a trend toward an increase in heart-rate AUC, with P = .070. No significant changes occurred in stroke volume. Although vitamin K2 supplementation has previously been reported to improve cardiovascular function in diseased patients, to the research team's knowledge, the current study is the first to report its potential in active individuals. More research is needed to fully evaluate the potential effects of the observed effects.

Murshed M. 2017. Bone mineralization. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a031229.

Mouton-Liger F, Jacoupy M, Corvol J-C, Corti O.  PINK1/Parkin-dependent mitochondrial surveillance: from pleiotropy to Parkinson’s disease.  Front Mol Neurosci.  2017 May 1;10:120.
Parkinson's disease (PD) is one of the most frequent neurodegenerative disease caused by the preferential, progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra (SN) pars compacta. PD is characterized by a multifaceted pathological process involving protein misfolding, mitochondrial dysfunction, neuroinflammation and metabolism deregulation. The molecular mechanisms governing the complex interplay between the different facets of this process are still unknown.  In this review, we illustrate the central role of this multifunctional pathway at the crossroads between mitochondrial stress, neuroinflammation and metabolism. We discuss how its dysfunction may contribute to PD pathogenesis and pinpoint major unresolved questions in the field.

Mozos I, Malainer C, Horbańczuk J, Gug C, Stoian D, Luca CT.  Inflammatory markers for arterial stiffness in cardiovascular diseases.  Front Immunol.  2017 Aug 31;8:1058.
There is strong evidence that inflammation plays an important and, at least, partly reversible role in the development of arterial stiffness, and inflammatory markers may be useful additional tools in the assessment of the cardiovascular risk in clinical practice. Combined assessment of arterial stiffness and inflammatory markers may improve non-invasive assessment of cardiovascular risk, enabling selection of high-risk patients for prophylactic treatment or more regular medical examination. Development of future destiffening therapies may target pro-inflammatory mechanisms.

Murshed M. Bone mineralization. Cold Spring Harb Perspect. Med. 2018 Dec;8(12):a031229. 
Mineralized "hard" tissues of the skeleton possess unique biomechanical properties to support the body weight and movement and act as a source of essential minerals required for critical body functions. For a long time, extracellular matrix (ECM) mineralization in the vertebrate skeleton was considered as a passive process. However, the explosion of genetic studies during the past decades has established that this process is essentially controlled by multiple genetic pathways. More recently, intracellular enzyme regulators of skeletal tissue mineralization have been identified. The current review will discuss the key determinants of ECM mineralization in bone and propose a unified model explaining this process.,

Pileggi CA, Parmar G, Harper ME.  The lifecycle of skeletal muscle mitochondria in obesity.  Obes Rev. 2021;22(5):313164.
Skeletal muscle possesses dramatic metabolic plasticity that allows for the rapid adaptation in cellular energy transduction to meet the demands of the organism. Obesity elicits changes in skeletal muscle structure and function, resulting in the accumulation of intramuscular lipids. The accumulation of intramuscular lipids in obesity is associated with impaired skeletal muscle mitochondrial content and function. Mitochondria exist as a dynamic network that is regulated by the processes of biogenesis, fusion, fission, and mitophagy. In this review, we outline adaptations in molecular pathways that regulate mitochondrial structure and function in obesity. We highlight the emerging role of dysregulated skeletal muscle macroautophagy and mitochondrial turnover in obesity.

Piscaer I, Drummen NE, van den Ouweland JM, Spanbroek M, Bloem-de Vries L, Franssen FM, et al.  The effect of vitamin K antagonists on rates of elastin degradation: potential implications for chronic pulmonary diseases.  Am J Respir Crit Care Med. 2017;195:A1053.
Elastin degradation is accelerated in both patients with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Desmosine (DES) is unique to elastin, and consequently, plasma (p)DES levels reflect the rate of elastin degradation. pDES is a strong predictor of mortality in COPD. Recently, we found an inverse association between vitamin K-status and the rate of elastin degradation in both patients with COPD and controls with no lung disease. Vitamin K-antagonists (VKAs, aka warfarin) are anticoagulant drugs that inhibit the recycling of vitamin K leading to vitamin K-deficiency. The use of VKAs is associated with increased mortality in patients with IPF. We hypothesized that VKAs have an unfavorable accelerating effect on elastin degradation. 106 consecutive subjects (75 males; 72±10 years) who had their international normalized ratio (INR) tested at the local anticoagulation clinic were included. A historical control group consisting of 181 subjects (83 males; 61±7 years) was used for Desphospho-uncarboxylated (dp-uc; i.e. inactive) Matrix Gla Protein (MGP) is formed during vitamin K-insufficiency. Dp-ucMGP levels are inversely correlated with vitamin K-status. Significant higher ln(pDES) was found in vitamin K antagonist-users compared to non-VKA users

Piscaer I, Wouters EFM, Vermeer C, Janssens, Franssen FME, Janssen R.  Vitamin K deficiency:  the linking pin between COPD and cardiovascular diseases?  Respir Res.  2017;18:189.
Vitamin K consumption, on the other hand, seems to have a protective effect on the mineralization of arteries. Furthermore, vascular calcification mutually relates to elastin degradation, which is accelerated in patients with COPD associating with impaired survival. In this commentary, we hypothesize that vitamin K is a critical determinant to the rate of elastin degradation. We speculate on the potential link between poor vitamin K status and crucial mechanisms of COPD pathogenesis and raise concerns about the use of VKAs in patients with this disease. Future intervention studies are needed to explore if vitamin K supplementation is able to reduce elastin degradation and vascular calcification in COPD patients.

Shea MK, Booth SL, Weiner DE, Brinkley TE, Kanaya AM, Murphy RA, et al. Circulating vitamin K is inversely associated with incident cardiovascular disease risk among those treated for hypertension in the Health, Aging, and Body Composition Study (Health ABC) J Nutr. 2017;147:888–895.
A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk. They looked at the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status. 0.72). Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension.

Ploumi C, Daskalaki I, Tavernarakis N. Mitochondrial biogenesis and clearance: A balancing act. FEBS J. 2017;284:183–195.
The generation of new and the removal of damaged or unwanted mitochondria are highly regulated processes that need to be accurately coordinated for the maintenance of mitochondrial and cellular homeostasis. Here, we survey recent research findings that advance our understanding and highlight the importance of the underlying molecular mechanisms.

Qiu C, Zheng H, Tao H, Yu W, Jiang X, Li A, et al.  Vitamin K2 inhibits rat vascular smooth muscle cell calcification by restoring the Gas6/Axl/Akt anti-apoptotic pathway.  Mol & Cell Biochem.  2017;433(1-2):149-159.

Vega RB, Konhilas JP, Kelly DP, Leinwand LA. Molecular mechanisms underlying cardiac adaptation to exerciseCell Metab. 2017;25:1012–26.
Exercise elicits coordinated multi-organ responses including skeletal muscle, vasculature, heart, and lung. In the short term, the output of the heart increases to meet the demand of strenuous exercise. Long-term exercise instigates remodeling of the heart including growth and adaptive molecular and cellular re-programming. They summarize the current understanding of the structural and functional cardiac responses to exercise as well as signaling pathways and downstream effector molecules responsible for these adaptations.

Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barners PJ, Bourbeau J, et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report.  Pulmonary Perspective.  2017;195(5):557-582.

Whyte MP. Hypophosphatasia: an overview for 2017. Bone.  2017 Sep;102:15-25.

Zhang Y-L, Yin J-H, Ding H, Zhang W, Zhang C-Q, Gao Y-S.  Protective effect of VK2 on glucocorticoid-treated MC3T3-E1 cells.  Int J Mol Med.  2017;39(1):160-166.
Glucocorticoids (GCs) contribute to the increased incidence of secondary osteoporosis and osteonecrosis, and medications for the prevention and treatment of these complications have been investigated for many years. Vitamin K2 (VK2) has been proven to promote bone formation both in vitro and in vivo. In this study, we examined the effects of VK2 on dexamethasone (DEX)-treated MC3T3-E1 osteoblastic cells Their findings indicate that VK2 may prove to be a promising agent for the prevention and treatment of GC-induced osteoporosis and osteonecrosis.

Akbari S, Rasouli-Ghahroudi AA. Vitamin K and bone metabolism: a review of the latest evidence in preclinical studies. Biomed Res Int2018;2018:4629383. 
Bone is a metabolically active tissue that renews itself throughout one's life. Cytokines along with several hormonal, nutritional, and growth factors are involved in tightly regulated bone remodeling. Accordingly, vitamin K as a multifunctional vitamin has been recently deemed appreciable as a topic of research as it plays a pivotal role in maintenance of the bone strength, and it has been proved to have a positive impact on the bone metabolism. Vitamin K exerts its anabolic effect on the bone turnover in different ways such as promoting osteoblast differentiation, upregulating transcription of specific genes in osteoblasts, and activating the bone-associated vitamin k dependent proteins which play critical roles in extracellular bone matrix mineralization. The main objective of the present paper is to comprehensively outline the preclinical studies on the properties of vitamin K and its effects on the bone metabolism. The evidence could shed light on further clinical studies to improve osteogenesis in bone graft surgeries.

Anzell A, Maizy R, Przyklenk K, Sanderson T. Mitochondrial quality control and disease: insights into Ischemia-Reperfusion injury. Mol Neurobiol. 2018;55:2547–2564.
This review aims to provide a synopsis of the molecular mechanisms involved in mitochondrial quality control, to summarize our current understanding of the complex role that mitochondrial quality control plays in the progression of acute vs chronic diseases and, finally, to speculate on the possibility that targeted manipulation of mitochondrial quality control mechanisms may be exploited for the rationale design of novel therapeutic interventions.

Ballegooijena AJ, Puttena SR, Vissera M, et al.  Vitamin K status and physical decline in older adults- The Longitudinal Aging Study of Amsterdam.  Maturitas.  2018;113:73-79.
They examined the association between vitamin K status and physical functioning over 13 years in the Longitudinal Aging Study Amsterdam. Low vitamin K status was associated with lower handgrip strength, smaller calf circumference, and, in women only, with poorer functional performance score. A low vitamin K status was however not related to the 13-year decline in these measures.

Cocciolone AJ, Hawes JZ, Staiculescu MC, Johnson EO, Murshed M, Waganseil JE.  Elastin, arterial mechanics, and cardiovascular disease.  Extracell Matrix in Cardiov Pathophysio.  2018;315(2):H189-H205.
Large, elastic arteries are composed of cells and a specialized extracellular matrix that provides reversible elasticity and strength. Elastin is the matrix protein responsible for this reversible elasticity that reduces the workload on the heart and dampens pulsatile flow in distal arteries. Here, we summarize the elastin protein biochemistry, self-association behavior, cross-linking process, and multistep elastic fiber assembly that provide large arteries with their unique mechanical properties. We briefly summarize challenges and recent advances in generating functional elastic fibers in tissue-engineered arteries. We conclude with suggestions for future research and opportunities for therapeutic intervention in genetic and acquired elastinopathies.

Cui L, Xu J, Zhang J, Zhang M, Zhang S, Bai Y.  Menaquinone-4 modulates the expression levels of calcification-associated factors to inhibit calcification of rat aortic vascular smooth muscle cells in a dose-dependent manner.  Experimental and Therapeutic Med.  2018;16(4):3172-3178.

Delezie J, Handschin C.  Endocrine crosstalk between skeletal muscle and the brain.  Front Neurol.  2018 Aug 24;9:698.
Skeletal muscle is an essential regulator of energy homeostasis and a potent coordinator of exercise-induced adaptations in other organs including the liver, fat or the brain. Skeletal muscle-initiated crosstalk with other tissues is accomplished though the secretion of myokines, protein hormones which can exert autocrine, paracrine and long-distance endocrine effects. In addition, the enhanced release or uptake of metabolites from and into contracting muscle cells, respectively, likewise can act as a powerful mediator of tissue interactions, in particular in regard to the central nervous system. The present review will discuss the current stage of knowledge regarding how exercise and the muscle secretome improve a broad range of brain functions related to vascularization, neuroplasticity, memory, sleep and mood. Physical activity represents one of the most effective strategies to reduce the prevalence and incidence of depression, cognitive, metabolic or degenerative neuronal disorders, and thus warrants further study.

Fontana L. Interventions to promote cardiometabolic health and slow cardiovascular ageingNat Rev Cardiol. (2018) 15:566–77.
Cardiovascular ageing and the atherosclerotic process begin very early in life, most likely in utero. They progress over decades of exposure to suboptimal or abnormal metabolic and hormonal risk factors, eventually culminating in very common, costly, and mostly preventable target-organ pathologies, including coronary heart disease, stroke, heart failure, aortic aneurysm, peripheral artery disease, and vascular dementia. In this Review, we discuss findings from preclinical and clinical studies showing that calorie restriction (CR), intermittent fasting, and adjusted diurnal rhythm of feeding, with adequate intake of specific macronutrients and micronutrients, are powerful interventions not only for the prevention of cardiovascular disease but also for slowing the accumulation of molecular damage leading to cardiometabolic dysfunction. Furthermore, we discuss the mechanisms through which a number of other nondietary interventions, such as regular physical activity, mindfulness-based stress-reduction exercises, and some CR-mimetic drugs that target pro-ageing pathways, can potentiate the beneficial effects of a healthy diet in promoting cardiometabolic health.

Hargreaves M, Spriet LL.  Exercise metabolism:  fuels for the fire.  Cold Spring Harbor Perspectives in Medicine.  2018;8(8):a029744.
During exercise, the supply of adenosine triphosphate (ATP) is essential for the energy-dependent processes that underpin ongoing contractile activity. These pathways involve both substrate-level phosphorylation, without any need for oxygen, and oxidative phosphorylation that is critically dependent on oxygen delivery to contracting skeletal muscle by the respiratory and cardiovascular systems and on the supply of reducing equivalents from the degradation of carbohydrate, fat, and, to a limited extent, protein fuel stores. The relative contribution of these pathways is primarily determined by exercise intensity, but also modulated by training status, preceding diet, age, gender, and environmental conditions. Optimal substrate availability and utilization before, during, and after exercise is critical for maintaining exercise performance. This review provides a brief overview of exercise metabolism, with expanded discussion of the regulation of muscle glucose uptake and fatty acid uptake and oxidation.

Jaghsi S, Hammoud T, Haddad S. Relation between circulating vitamin K1 and osteoporosis in the lumbar spine in Syrian post-menopausal women. The Open Rheumatology Journal2018;12(1):1–9.
In the past two decades, Vitamin K has been receiving more attention due to its role in bone health and metabolism. The bone mineral density does not remain steady with age, particularly declining after menopause.This study is aimed to investigate the relationship between bone mineral density and serum vitamin K1 levels in post-menopausal women, and to evaluate serum vitamin K1 levels as a potential biomarker for postmenopausal osteoporosis.Our results suggest that vitamin K1 may contribute to maintain bone mineral density. Vitamin K1 may have a role in diagnosing post-menopausal osteoporosis. Vitamin K1 may be a valuable diagnostic as well as therapeutic marker in post-menopausal osteoporosis.

Karsenty G, Mera P.  Molecular bases of the crosstalk between bone and muscle.  Bone. 2018 Oct;115:43-49.
Exercise is survival function that has beneficial health effects. The increased metabolic activity of contracting skeletal muscle affects the biology of many organs involved in regulating muscle functions. The discovery of hormones and cytokines secreted by bone and skeletal muscle during exercise, has recently added credence to the notion that a crosstalk exists between these organs. Bone through the hormone osteocalcin, promotes exercise capacity in the mouse. After binding to a G-coupled protein receptor, Gprc6a, osteocalcin increases nutrients uptake and catabolism in myofibers during exercise. In addition, osteocalcin regulates the endocrine function of skeletal muscle because it enhances the expression of interleukin-6 (IL-6). IL-6 is produced and secreted by contracting skeletal muscle and exerts autocrine, paracrine and systemic effects. One of the systemic functions of IL-6 is to drive the generation of bioactive osteocalcin. Altogether, these studies have revealed a feed-forward loop between bone and skeletal muscle that are necessary and sufficient for optimum exercise capacity. This endocrine regulation of exercise biology, suggest novel and adapted strategies for the prevention or treatment of age-related muscle loss.

Lin X, Brennan-Speranza TC, Levinger I, Yeap BB.  Undercarboxylated osteocalcin:  experimental and human evidence for a role in glucose homeostasis and muscle regulation of insulin sensitivity.  Nutrients.  2018;10:847.  
Recent advances have indicated that osteocalcin, and in particular its undercarboxylated form (ucOC), is not only a nutritional biomarker reflective of vitamin K status and an indicator of bone health but also an active hormone that mediates identification of (GPRC6A) as a cell surface receptor for ucOC. Of note, ucOC has been associated with diabetes and with cardiovascular risk in epidemiological studies, consistent with a pathophysiological role for ucOC in vivo. A key emerging area of research is the role of ucOC in muscle, and whether exercise interventions may modulate metabolic outcomes favorably via ucOC.

Luo Y, Li N, Chen H, Fernandez GE, Warburton D, Moats R, Mecham RP, et al.  Spatial and temporal changes in extracellular elastin and laminin distribution during lung alveolar development.  Sci Rep.  2018 May 29;8(1):8334.

Mecham RP.  Elastin in lung development and disease pathogenesis.  Matrix Biol.  2018 Nov;73:6-20. 
Elastin is expressed in most tissues that require elastic recoil. Elastin is expressed by multiple cell types in the lung, including mesothelial cells in the pleura, smooth muscle cells in airways and blood vessels, endothelial cells, and interstitial fibroblasts. Elastic fibers can be woven into many different shapes depending on the mechanical needs of the tissue. In large pulmonary vessels, for example, elastin forms continuous sheets, or lamellae, that separate smooth muscle layers. Outside of the vasculature, elastic fibers form an extensive fiber network that originates in the central bronchi and inserts into the distal airspaces and visceral pleura. Normal lung function depends on proper secretion and assembly of elastin, and either inhibition of elastin fiber assembly or degradation of existing elastin results in lung dysfunction and disease.

Mera P, Ferron M, Mosialou J.  Regulation of energy metabolism by Bone-Derived Hormones.  Cold Spring Harb Perspect Med. 2018 Jun;8(6):a031666.
Like many other organs, bone can act as an endocrine organ through the secretion of bone-specific hormones or “osteokines.” At least two osteokines are implicated in the control of glucose and energy metabolism: osteocalcin (OCN) and lipocalin-2 (LCN2). OCN stimulates the production and secretion of insulin by the pancreatic β-cells, but also favors adaptation to exercise by stimulating glucose and fatty acid (FA) utilization by the muscle. Both of these OCN functions are mediated by the G-protein-coupled receptor GPRC6A. In contrast, LCN2 influences energy metabolism by activating appetite-suppressing signaling in the brain.

Moser SC, van der Eerden BCJ.  Osteocalcin-a versatile bone-derived hormone.  Front Endocrinol (Lausanne).  2018;9:794.
Bone has long been regarded as a static organ, simply providing protection and support. However, this mindset has changed radically in recent years and bone is becoming increasingly recognized for its endocrine function of secreting several hormones, thereby controlling various physiological pathways. One of the factors released by the skeleton is osteocalcin.  It has been reported to control several physiological processes in an endocrine manner, such as glucose homeostasis and exercise capacity, brain development, cognition, and male fertility. The aim of this review is to provide an overview of the currently known roles of osteocalcin and their underlying mechanisms.

Piscaer I, Kalkman GA, Fleuren HW, Janssens W, Wouters EF,  Franssen FM, et al.  Use of vitamin K antagonists Is associated with increased mortality in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2018;197:A4234.
Elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD) and related to mortality. Vascular calcification is also enhanced and inversely related to survival in COPD patients. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of arterial calcification and elastin degradation. Vitamin K antagonists (VKAs) inhibit vitamin K recycling thereby inducing vitamin K deficiency leading to insufficient MGP activation and, consequently, promotion of both arterial calcification and elastin degradation. The use of VKAs in patients with idiopathic pulmonary fibrosis is associated with increased mortality.  The aim of this study was to investigate mortality risk in COPD patients with and without VKAs.  They found that vitamin K antagonist’s use was associated with increased mortality in our COPD cohort. It is plausible that the underlying pathogenic mechanisms are stimulation of both elastin degradation and vascular calcification by VKAs.

Popko J, Karpinski M, Chojnowska S, Maresz K, Milewski R, Badmaev V, et al.  Decreased levels of circulating carboxylated osteocalcin in children with low energy fractures:  a pilot study.  Nutrients.  2018;10:734.
In the past decades, an increased interest in the roles of vitamin D and K has become evident, in particular in relation to bone health and prevention of bone fractures. The aim of the current study was to evaluate vitamin D and K status in children with low-energy fractures and in children without fractures. This pilot study found that better vitamin K status is positively and significantly correlated with lower rate of low-energy fracture incidence.

Rønning SB, Pedersen ME, Berg RS, Kirkhus B, Rødbotten R.  Vitamin K2 improves proliferation and migration of bovine skeletal muscle cells in vitro.  PLoS One.  2018;13(4):E0195432.
Skeletal muscle function is highly dependent on the ability to regenerate, however, during aging or disease, the proliferative capacity is reduced, leading to loss of muscle function. In this study, primary bovine skeletal muscle cells, was used to assess a potential effect of vitamin K2 (MK-4) during myogenesis of muscle cells. Cytotoxicity analysis show that MK-4 reduced the lactate dehydrogenase (LDH) released into the media, suggesting that MK-4 was beneficial to the muscle cells. Adding MK-4 to the cells led to an increased muscle proliferation, increased gene expression of the myogenic transcription factor myod as well as increased cell migration. MK-4 plays a significant role during the early phases of muscle proliferation. Likewise, we see the same pattern for the relative gene expression of collagen 1A, showing increased gene expression in proliferating cells, and reduced expression in differentiating cells. Altogether, our experiments show that MK-4 has a positive effect on muscle cell migration and proliferation, which are two important steps during early myogenesis or muscle cell creation.

Shearer MJ, Okano T. Key pathways and regulators of vitamin K function and intermediary metabolism. Annu Rev Nutr United States. 2018;38:127–151.
Vitamin K (VK) is an essential cofactor for the conversion of glutamate to γ-carboxyglutamate. The resultant vitamin K-dependent proteins are known to possess a variety of biological functions. The vitamin K cycle is a cellular pathway that drives γ-carboxylation and recycling of VK via γ-carboxyglutamyl carboxylase (GGCX) and vitamin K epoxide reductase (VKOR), respectively. In this review, we discuss how other protein regulators influence the intermediary metabolism of VK, first through intestinal absorption and second through a pathway that converts some dietary phylloquinone to menadione, which is prenylated to menaquinone-4 (MK-4) in target tissues by UBIAD1. The contribution of MK-4 synthesis to VK functions is yet to be revealed.

Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol.  2018;20:745–754. 

Strasser B, Burtscher M.  Survival of the fittest:  VO2 max, a key predictor of longevity?  Frontiers in Biosci, Landmark. 2018 Mar;23:1505-1516.
Cardiorespiratory fitness, as measured by maximal oxygen uptake (VO2 max), is related to functional capacity and human performance and has been shown to be a strong and independent predictor of all-cause and disease-specific mortality. The purpose of this review is to emphasize age-related physiological adaptations that occur with regular exercise training, with specific reference to the main organs (lung, heart, skeletal muscles) involved in oxygen delivery and utilization. As yet, it is not possible to extend the genetically fixed lifespan with regular exercise training, but to give the years more life. This is where physical fitness plays an important role.

Uwitonze AM, Razzaque MS. Role of Magnesium in vitamin D activation and function. J Am Osteopat Assoc. 2018;118:181–189.
Nutrients usually act in a coordinated manner in the body. Intestinal absorption and subsequent metabolism of a particular nutrient, to a certain extent, is dependent on the availability of other nutrients. Magnesium and vitamin D are 2 essential nutrients that are necessary for the physiologic functions of various organs. Magnesium assists in the activation of vitamin D, which helps regulate calcium and phosphate homeostasis to influence the growth and maintenance of bones. All of the enzymes that metabolize vitamin D seem to require magnesium, which acts as a cofactor in the enzymatic reactions in the liver and kidneys. Deficiency in either of these nutrients is reported to be associated with various disorders, such as skeletal deformities, cardiovascular diseases, and metabolic syndrome. It is therefore essential to ensure that the recommended amount of magnesium is consumed to obtain the optimal benefits of vitamin D.

Van Ballegooijen AJ, van Putten SR, Visser M, Beulens JW, Hoogendijk EO.  Vitamin K status and physical decline in older adults – The Longitudinal Aging Study Amsterdam.  Maturitas.  2018 Jul;113:73-79.
We examined the association between vitamin K status and physical functioning over 13 years in the Longitudinal Aging Study Amsterdam.  They concluded that low vitamin K status was associated with lower handgrip strength, smaller calf circumference, and, in women only, with poorer functional performance score.

Vermeer C, Raes J, van’t Hoofd C, Knapen MHJ, Xanthoulea S.  Menaquinone content of cheese.  Nutrients.  2018 Apr 4;10(4):446.
Vitamin K₂ (menaquinone) concentrations were measured in a wide range of cheeses and the effects of fat content, ripening and origin of the cheeses were investigated. Moreover, the menaquinone content of cheese was compared with that of other foods known to contain vitamin K₂. It was found that cheese and curd are the most important sources of long-chain menaquinones in the Western diet and, in general, hard cheeses are richer in menaquinones than soft cheeses. However, the actual menaquinone content varies substantially and is dependent on the type of cheese, the time of ripening, the fat content and the geographic area where the cheeses are produced. Given the fact that poor vitamin K status has been mentioned as a risk factor for cardiovascular disease and mortality, while there is no clear evidence for adverse cardiovascular effects of dairy fats, cheese should be considered as a recommendable component in a heart-healthy diet.

Wen L, Chen J., Duan L., Li S. Vitamin K‑dependent proteins involved in bone and cardiovascular health (Review) Mol. Med. Rep. 2018;18:3–15.
A total of 17 different vitamin K‑dependent proteins have been identified to date. Vitamin K‑dependent proteins are located within the bone, heart and blood vessels. For instance, carboxylated osteocalcin is beneficial for bone and aids the deposition of calcium into the bone matrix. These vitamin K‑dependent proteins may exert their functions following γ‑carboxylation with vitamin K, and different vitamin K‑dependent proteins may exhibit synergistic effects or antagonistic effects on each other. In the cardiovascular system with vitamin K antagonist supplement or vitamin K deficiency, calcification occurs in the endothelium of blood vessels and vascular smooth muscle cells are transformed into osteoblast‑like cells, a phenomenon that resembles bone growth.  The results of the review suggest that the vascular calcification and osteogenic differentiation of vascular smooth muscle cells may be associated with the location of the bone and cardiovascular system during embryonic development.

Azuma K, Inoue S.  Multiple modes of vitamin K actions in aging-related musculoskeletal disorders.  Int J Mole Sci.  2019;20:2844.
Vitamin K is a fat-soluble vitamin that was originally found as an essential factor for blood coagulation. Over the last two decades, other modes of vitamin K actions have been discovered and several epidemiological studies have revealed that vitamin K status is associated with some aging-related diseases including osteoporosis, osteoarthritis, and sarcopenia. In clinical studies on osteoarthritis, the γ-carboxylation of matrix Gla protein (MGP) and gla-rich protein (GRP) may have a protective role for the disease. In the case of sarcopenia, a high vitamin K status in plasma was associated with muscle strength, large muscle mass, and high physical performance in some observational studies. Further research on vitamin K will clarify new biological mechanisms which contribute to human longevity and health through the prevention and treatment of aging-related musculoskeletal disorders.

Burtscher J, Ruedl G, Posch M, Greier K, Burtscher M. The upper limit of cardiorespiratory fitness associated with longevity: An update. AIMS Public Health2019;6:225–228.
Consequently, both a CRF level as high as possible during early adulthood, achieved by appropriate exercise interventions, and a small CRF decline during later life, by continuation of regular physical activity, will help to optimize longevity.

Casuso RA, Huertas JR, Agustín, PH, Cogliati S.  Stay Fit, Stay Young: Mitochondria in Movement: The Role of Exercise in the New Mitochondrial Paradigm.  Oxid Med.  2019 Jun 19;19(9):1-18.
Skeletal muscles require the proper production and distribution of energy to sustain their work. To ensure this requirement is met, mitochondria form large networks within skeletal muscle cells, and during exercise, they can enhance their functions. In the present review, we discuss recent findings on exercise-induced mitochondrial adaptations. We emphasize the importance of mitochondrial biogenesis, morphological changes, and increases in respiratory supercomplex formation as mechanisms triggered by exercise that may increase the function of skeletal muscles. Finally, we highlight the possible effects of nutraceutical compounds on mitochondrial performance during exercise and outline the use of exercise as a therapeutic tool in noncommunicable disease prevention. The resulting picture shows that the modulation of mitochondrial activity by exercise is not only fundamental for physical performance but also a key point for whole-organism well-being

Cerqua C, Casarin A, Pierrel F, Fonseca LV, Viola G, Salviati L, Trevisson E.  Vitamin k2 cannot substitute Coenzyme Q10 as electron carrier in the mitochondrial respiratory chain of mammalian cells.  Scientific Reports.  2019;9:6553.

Crintea A, Dutu AG, Masalar AL, Linga E, Constantin A-M, Craciun A.  Vitamin K in sport activities:  a less considered benefit for athletic training.  HSRM Health, Sports & Rehabilitation Medicine.  2019 Jan;22(2):127-132.
Vitamin K and its dependent proteins have important roles in several physiological or tumoral processes: bone mineralization, blood clotting, metabolism of blood vessel walls, tumoral angiogenesis and even cell growth and nervous system biochemistry (aspects of behavior and cognition). Vitamin K deficiency is associated with several diseases, including osteoporosis, vascular calcification and even depression. Through its involvement in cardiovascular and nervous system function, and bone metabolism, vitamin K supplementation could improve exercise capacity.

Diaz-Franco MC, Franco-Diaz de Leon R, Villafan-Bernal JF.  Osteocalcin-GPRC6Z:  an update of its clinical and biological multi-organic interactions (Review).  Mol Med Rep. 2019 Jan;19(1):15-22. 
Osteocalcin is no longer regarded as a molecule exclusive to bone remodeling and osteogenesis, but as a hormone with manifold functions. The discovery of the interaction of osteocalcin with the G protein‑coupled receptor family C group 6‑member A (GPRC6A) receptor has accompanied the characterization of several roles that this peptide serves in body regulation and homeostasis. These roles include the modulation of memory in the brain, fertility in the testis, fat accumulation in the liver, incretins release in the intestine and adaptation to exercise in muscle, in addition to the well‑known effects on β‑cell proliferation, insulin release and adiponectin secretion. The aim of the present review was to provide a practical update of the multi‑organ effects that osteocalcin exerts through its interaction with GPRC6A and the clinical implications of this.

Griffin TP, Islam MN, Wall D, Ferguson J, Griffin DG, Griffin MD, O’Shea PM.  Plasma dephosphorylated-uncarboxylated matrix Gla-protein (dp-ucMGP):  reference intervals in Caucasian adults and diabetic kidney disease biomarker potential.  Scientific Reports.  2019;9(1):18542.

Hiam D, Voisin S, Yan, XU, Landen S, Jacques M, Papadimitriou ID, et al.  The association between bone mineral density gene variants and osteocalcin at baseline, and in response to exercise:The gene SMART study.  Bone.  2019 Jun;123:23-27.

Hood DA, Memme JM, Oliveira AN, Triolo M.  Maintenance of skeletal muscle mitochondria in health, exercise, and aging.  Annu Rev Physiol.  2019 Feb 10;81:19-41.
Mitochondria are critical organelles responsible for regulating the metabolic status of skeletal muscle. These organelles exhibit remarkable plasticity by adapting their volume, structure, and function in response to chronic exercise, disuse, aging, and disease. A single bout of exercise initiates signaling to provoke increases in mitochondrial biogenesis, balanced by the onset of organelle turnover carried out by the mitophagy pathway. This accelerated turnover ensures the presence of a high functioning network of mitochondria designed for optimal ATP supply, with the consequence of favoring lipid metabolism, maintaining muscle mass, and reducing apoptotic susceptibility over the longer term. Conversely, aging and disuse are associated with reductions in muscle mass that are in part attributable to dysregulation of the mitochondrial network and impaired mitochondrial function. Therefore, exercise represents a viable, nonpharmaceutical therapy with the potential to reverse and enhance the impaired mitochondrial function observed with aging and chronic muscle disuse.

Huertas JR, Casuso RA, Agustin PH, Cogliati S.  Corrigdendum to “Stay fit, stay young:  mitochondria in movement:  the role of exercise in the new mitochondrial paradigm”.  Oxid Med Cell Longev. 2021;2021:9274841. 

Kojima A, Ikehara S, Kamiya K, Kajita E, Sato Y, Kouda K, et al. Natto intake is inversely associated with osteoporotic fracture risk in postmenopausal Japanese women. J Nutr. 2019;150:599–605.
The direct association between intake of Japanese fermented soybeans, namely natto, and bone mineral density (BMD) is known. However, the association with osteoporotic fractures has not been studied. Habitual natto intake may be associated with a reduced risk of osteoporotic fractures independent of confounding factors, including BMD, in Japanese postmenopausal women. 

Lees JS, Chapman FA, Witham MD, Jardine AG, Mark PB. Vitamin K status, supplementation and vascular disease: a systematic review and meta-analysis. Heart. 2019;105:938–945. 

Lombardi G. Exercise-dependent modulation of bone metabolism and bone endocrine function: new findings and therapeutic perspectives. J Sci Sport Exerc. 2019;1:20–28.

Memme JM, Erlich AT, Phukan G, Hood DA.  Exercise and mitochondrial health.  J of Physio.  2019 Nov;599(3):803-817.  
Mitochondrial health is an important mediator of cellular function across a range of tissues, and as a result contributes to whole-body vitality in health and disease. Our understanding of the regulation and function of these organelles is of great interest to scientists and clinicians across many disciplines within our healthcare system. Skeletal muscle is a useful model tissue for the study of mitochondrial adaptations because of its mass and contribution to whole body metabolism. The remarkable plasticity of mitochondria allows them to adjust their volume, structure and capacity under conditions such as exercise, which is useful or improving metabolic health in individuals with various diseases and/or advancing age. Mitochondria exist within muscle as a functional reticulum which is maintained by dynamic processes of biogenesis and fusion, and is balanced by opposing processes of fission and mitophagy. To this point, exercise remains the most potent behavioural therapeutic approach for the improvement of mitochondrial health, not only in muscle, but potentially also in other tissues.

Oliveira AN, Hood DA.  Exercise is mitochondrial medicine for muscle.  Sports Med & Health Science.  2019;1:11-18.
Mitochondria are vital organelles that provide energy for muscle function. When these organelles become dysfunctional, they produce less energy as well as excessive levels of reactive oxygen species which can trigger muscle atrophy, weakness and loss of endurance. In this review, molecular evidence is provided to show that exercise serves as a useful therapeutic countermeasure to overcome mitochondrial dysfunction, even when key regulators of organelle biogenesis are absent. These findings illustrate the complexity and compensatory nature of exercise-induced molecular signaling to transcription, as well as to post-transcriptional events within the mitochondrial synthesis and degradation (i.e. turnover) pathways. Beginning with the first bout of contractile activity, exercise exerts a medicinal effect to improve mitochondrial health and whole muscle function.

Pinckard K, Baskin KK, Stanford KI.  Effects of exercise to improve cardiovascular health.  Front Cardiovas Med.  2019;6:69.
Obesity is a complex disease that affects whole body metabolism and is associated with an increased risk of cardiovascular disease (CVD) and Type 2 diabetes (T2D). Physical exercise results in numerous health benefits and is an important tool to combat obesity and its co-morbidities, including cardiovascular disease. Exercise prevents both the onset and development of cardiovascular disease and is an important therapeutic tool to improve outcomes for patients with cardiovascular disease. Some benefits of exercise include enhanced mitochondrial function, restoration and improvement of vasculature, and the release of myokines from skeletal muscle that preserve or augment cardiovascular function. In this review we will discuss the mechanisms through which exercise promotes cardiovascular health.

Piscaer I, van den Ouweland JMW, Vermeersch K, Reynaert NL, Franssen FME, Keene S, et al.  Low vitamin K status is associated with increased elastin degradation in chronic obstructive pulmonary disease.  J Clin Med.  2019 Jul 27;8(8):1116.
In conclusion, we demonstrated reduced vitamin K status in COPD and an inverse association between vitamin K status and elastin degradation rate. Our results therefore suggest a potential role of vitamin K in COPD pathogenesis.

Roumeliotis, S, Dounousi, E, Eleftheriadis T, & Liakopoulos V. Association of the inactive circulating matrix Gla protein with vitamin K intake, calcification, mortality, and cardiovascular disease: A reviewInternational Journal of Molecular Sciences.  2019;20(3):628.
Matrix Gla Protein (MGP), a small Gla vitamin K-dependent protein, is the most powerful natural occurring inhibitor of calcification in the human body. To become biologically active, MGP must undergo vitamin K-dependent carboxylation and phosphorylation. Vitamin K deficiency leads to the inactive uncarboxylated, dephosphorylated form of MGP (dpucMGP). We aimed to review the existing data on the association between circulating dpucMGP and vascular calcification, renal function, mortality, and cardiovascular disease in distinct populations. Moreover, the association between vitamin K supplementation and serum levels of dpucMGP was also reviewed.

Si H, Ma P, Liang Q, Yin Y, Wang P, Shang Q, et al.  Overexpression of pink1 or parkin in indirect flight muscles promotes mitochondrial proteostasis and extends lifespan in Drosophila melanogaster.  PLoS One.  2019 Nov 12;14(11): e0225214.
Our study provides physiological evidence that mitophagy of mitochondrial ubiquitination mediated by PINK1/ Parkin is crucial for muscle function and highlights the role of mitophagy in the pathogenesis of chronic diseases like PD.

Simes DC, Viegas CSB, Araújo N, Marreiros C.  Vitamin K as a powerful micronutrient in age-related diseases:  pros and cons from clinical studies.  Int J Mol Sci.  2019;20(17):4150.
Vitamin K is a multifunctional micronutrient implicated in age-related diseases such as cardiovascular diseases, osteoarthritis and osteoporosis. Although vitamin K-dependent proteins (VKDPs) are described to have a crucial role in the pathogenesis of these diseases, novel roles have emerged for vitamin K, independently of its role in VKDPs carboxylation. Vitamin K has been shown to act as an anti-inflammatory by suppressing nuclear factor κB (NF-κB) signal transduction and to exert a protective effect against oxidative stress by blocking the generation of reactive oxygen species. Available clinical evidences indicate that a high vitamin K status can exert a protective role in the inflammatory and mineralization processes associated with the onset and progression of age-related diseases. Also, vitamin K involvement as a protective super-micronutrient in aging and ‘inflammaging’ is arising, highlighting its future use in clinical practice. In this review we summarize current knowledge regarding clinical data on vitamin K in skeletal and cardiovascular health, and discuss the potential of vitamin K supplementation as a health benefit. We describe the clinical evidence and explore molecular aspects of vitamin K protective role in aging and age-related diseases, and its involvement as a modulator in the interplay between pathological calcification and inflammation processes.

Sprenger H-G, Langer T.  The good and the bad of mitochondrial breakups.  Trends Cell Biol.  2019 Nov;29(11):888-900.

Wasilewski GB, Vervloet MG, Schurgers LJ.  The bone-vascular axis:  calcium supplementation and the role of vitamin K.  Frontiers in Cardiovascular Med.  2019;6(6):1.
Chronic kidney disease (CKD) patients are prone to vascular calcification in part due to impaired phosphate excretion. Calcium-based phosphate binders further increase risk of vascular calcification progression. In both bone and vascular tissue, vitamin K-dependent processes play an important role in calcium homeostasis and it is tempting to speculate that vitamin K supplementation might protect from the potentially untoward effects of calcium supplementation. This review provides an update on current literature on calcium supplementation among post-menopausal women and CKD patients and discusses underlying molecular mechanisms of vascular calcification. We propose therapeutic strategies with vitamin K2 treatment to prevent or hold progression of vascular calcification as a consequence of excessive calcium intake.

Wei F-F, Trenson S, Verhamme P, Vermeer C, Staessen JA.  Vitamin K-dependent matrix Gla protein as multifaceted protector of vascular and tissue integrity.  Hypertension.  2019 Jun;73(6):1160-1169.

Yoshioka K, Fujita R, Seko D, Suematsu T, Miura S, Ono Y. Distinct Roles of Zmynd17 and PGC1alpha in Mitochondrial Quality Control and Biogenesis in Skeletal Muscle. Front Cell Dev Biol. 2019;7:330.

Zhang S, Guo L, Bu, C. Vitamin K status and cardiovascular events or mortality: A meta-analysis. Eur J Prev Cardiol. 2019;26:549–553.

2020s

Battafarano G, Rossi M, Marampon F, Minisola F, Del Fattore A.  Bone control of muscle function.  Int J Mol Sci.  2020 Feb;21:1178.
Bone and muscle represent a single functional system and are tightly connected to each other. Indeed, diseases characterized by alterations of muscle physiology have effects on bone remodeling and structure and vice versa. Osteocalcin can exist in two forms with different degrees of carboxylation. The undercarboxylated form of osteocalcin is a hormone released by the bone matrix during the osteoclast bone resorption and can bind its G-protein coupled receptor GPRC6A expressed in the muscle, thus regulating its function. Recently, this hormone was described as an antiaging molecule for its ability to regulate bone, muscle and cognitive functions. Indeed, the features of this bone-related hormone were used to test a new therapeutic approach for sarcopenia, since injection of osteocalcin in older mice induces the acquirement of physical abilities of younger animals. Even if this approach should be tested in humans, osteocalcin represents the most surprising molecule in endocrine regulation by the skeleton.

Bultynck C, Munim N, Harrington D, Judd, L, Ataklte F, Shah Z, et al.  Prevalence of vitamin K deficiency in older people with hip fracture. Acta Clin Belg. 2020;75:136–140.

Casuso RA, Huertas JR.  The emerging role of skeletal muscle mitochondrial dynamics in exercise and ageing.  Aging Res Rev.  2020;58:101025.
Mitochondria are the hub for energy production within living cells. They can undergo morphological changes in response to nutrient availability and cellular stress. Here, we review how exercise chronically and acutely affects mitochondrial dynamics. Moreover, we discuss whether mitochondrial dysfunction observed in elderly subjects is due to the ageing process per se or due to the associated sedentary state. Finally, we study how endurance exercise can improve mitochondrial dynamics in older subjects, thereby improving their overall health and likely limiting muscle waste.

Chowdhury, S., et al., Muscle-derived interleukin 6 increases exercise capacity by signaling in 425 osteoblasts. J Clin Invest, 2020;130(6):2888-2902.

Ferron M, Wei J, Yoshizawa T, Fel Fattore A, DePhinho RA, Teti A, et al.  Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism.  Cell. 2020 July 23:142(2):296-308.
The broad expression of the insulin receptor suggests that the spectrum of insulin function has not been fully described. A cell type expressing this receptor is the osteoblast, a bone-specific cell favoring glucose metabolism through a hormone, osteocalcin, that becomes active once uncarboxylated. We show here that insulin signaling in osteoblasts is necessary for whole-body glucose homeostasis because it increases osteocalcin activity. To achieve this function insulin signaling in osteoblasts takes advantage of the regulation of osteoclastic bone resorption exerted by osteoblasts. Indeed, since bone resorption occurs at a pH acidic enough to decarboxylate proteins, osteoclasts determine the carboxylation status and function of osteocalcin. Accordingly, increasing or decreasing insulin signaling in osteoblasts promotes or hampers glucose metabolism in a bone resorption-dependent manner in mice and humans. Hence, in a feed-forward loop, insulin signals in osteoblasts activate a hormone, osteocalcin, that promotes glucose metabolism.

Fusaro M, Cianciolo, G, Brandi ML, Ferrari S, Nickolas TL, Tripepi G, Plebani, et al. Vitamin K and Osteoporosis. Nutrients 2020, 12, 3625.

Hargreaves M, Spriet LL.  Skeletal muscl;energy metabolism during exercise.  Nature Metabolism.  2020 Sep; 2:817-828.
The continual supply of ATP to the fundamental cellular processes that underpin skeletal muscle contraction during exercise is essential for sports performance in events lasting seconds to several hours. Because the muscle stores of ATP are small, metabolic pathways must be activated to maintain the required rates of ATP resynthesis. Here, we provide an overview of exercise metabolism and the key regulatory mechanisms ensuring that ATP resynthesis is closely matched to the ATP demand of exercise. We also summarize various interventions that target muscle metabolism for ergogenic benefit in athletic events.

Haugsgjerd TR, Egeland GM, Nygård OK, Vinknes KJ, Sulo G, Lysne V, et al.   Association of dietary vitamin K and risk of coronary heart disease in middle-age adults: The Hordaland Health Study Cohort. BMJ Open 2020, 10, e035953.
The role of vitamin K in the regulation of vascular calcification is established. However, the association of dietary vitamins K1 and K2 with risk of coronary heart disease (CHD) is inconclusive. They followed participants in the community-based Hordaland Health Study from 1997 - 1999 through 2009 to evaluate associations between intake of vitamin K and incident (new onset) coronary heart disease.  They found that a higher intake of vitamin K2 was associated with lower risk of CHD, while there was no association between intake of vitamin K1 and CHD.

Jaminion AMG, Dai L, Qureshi AR, Evenepoel P, Ripsweden J, Söderberg M, Witasp A.  Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease.  Sci Rep.  2020 Apr 20;10(1):6586.
Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. The results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Taken together, our results support that MGP is involved in the pathogenesis of VC.

Kirk B, Feehan J, Lombardi G, Duque G. Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and adipokines. Curr Osteoporos Rep. 2020;18:388–400.
Skeletal muscle and bone are connected anatomically and physiologically, and play a crucial role in human locomotion and metabolism. Historically, the coupling between muscle and bone has been viewed in light of mechanotransduction, which dictates that the mechanical forces applied to muscle are transmitted to the skeleton to initiate bone formation. However, these organs also communicate through the endocrine system, orchestrated by a family of cytokines namely myokines (derived from myocytes) and osteokines (derived from bone cells). A third player in this biochemical crosstalk is adipose tissue and the secretion of adipokines (derived from adipocytes). In this review, we discuss the bidirectional effects of myokines and osteokines on muscle and bone metabolism, and the impact of adipokines on both of these secretory organs.

Komori T.  Functions of osteocalcin in bone, pancreas, testis, and muscle.  Int J Mol Sci.  2020;21:7513.
Osteocalcin (Ocn), which is specifically produced by osteoblasts, and is the most abundant non-collagenous protein in bone, was demonstrated to inhibit bone formation and function as a hormone, which regulates glucose metabolism in the pancreas, testosterone synthesis in the testis, and muscle mass, based on the phenotype of Ocn−/− mice by Karsenty’s group. Recently, Ocn−/− mice were newly generated by two groups independently. Bone strength is determined by bone quantity and quality. The new Ocn−/− mice revealed that Ocn is not involved in the regulation of bone formation and bone quantity, but that Ocn regulates bone quality by aligning biological apatite (BAp) parallel to the collagen fibrils. Thus, the function of Ocn is the adjustment of growth orientation of BAp parallel to the collagen fibrils, which is important for bone strength to the loading direction of the long bone. However, Ocn does not play a role as a hormone in the pancreas, testis, and muscle. Clinically, serum Ocn is a marker for bone formation, and exercise increases bone formation and improves glucose metabolism, making a connection between Ocn and glucose metabolism.

Lacombe J, Al Rifai O, Loter L, Moran T, Turcotte A-F, Grenier-Larouche T, et al.  Measurement of bioactive osteocalcin in humans using a novel immunosassay reveals association with glucose metabolism and B-cell function.  Am J Physiol Endocrinol Metab.  2020 Mar 1;318(3):E381-E391.
Osteocalcin (OCN) is a bone-derived hormone involved in the regulation of glucose metabolism. In serum, OCN exists in carboxylated and uncarboxylated forms (ucOCN), and studies in rodents suggest that ucOCN is the bioactive form of this hormone. Whether this is also the case in humans is unclear, because a reliable assay to measure ucOCN is not available. Here, we established and validated a new immunoassay (ELISA) measuring human ucOCN and used it to determine the level of bioactive OCN in two cohorts of overweight or obese subjects, with or without type 2 diabetes (T2D). The ELISA could specifically detect ucOCN concentrations ranging from 0.037 to 1.8 ng/mL. In conclusion, ucOCN measured with this novel and specific assay is inversely associated with insulin resistance and β-cell dysfunction in humans.

Lin X, Onda D-A, Yang C-H, Lewis JR, Levinger I, Loh K.  Roles of bone-derived hormones in type 2 diabetes and cardiovascular pathophysiology.  Mol Metab.  2020 Oct;40:101040.
Emerging evidence demonstrates that bone is an endocrine organ capable of influencing multiple physiological and pathological processes through the secretion of hormones. Recent research suggests complex crosstalk between the bone and other metabolic and cardiovascular tissues. It was uncovered that three of these bone-derived hormones—osteocalcin, lipocalin 2, and sclerostin—are involved in the endocrine regulations of cardiometabolic health and play vital roles in the pathophysiological process of developing cardiometabolic syndromes such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation is one of the hallmarks of cardiometabolic diseases and a major contributor to disease progression. Novel evidence also implicates important roles of bone-derived hormones in the regulation of chronic inflammation.

Lu W, Ziao W, Zie W, Fu X, Pan L, Jin H, et al.  The role of osteodkines in sarcopenia:  therapeutic directions and application prospects.  Front. Cell Dev Biol.  2020;9:634374.
Sarcopenia is an age-related disease in which muscle mass, strength and function may decline with age or can be secondary to cachexia or malnutrition and can lead to weakness, falls and even death. With the increase in life expectancy, sarcopenia has become a major threat to the health of the elderly. Currently, our understanding of bone-muscle interactions is not limited to their mechanical coupling. Bone and muscle have been identified as secretory endocrine organs, and their interaction may affect the function of each. Both muscle-derived factors and osteokines can play a role in regulating muscle and bone metabolism via autocrine, paracrine and endocrine mechanisms. Herein, we comprehensively summarize the latest research progress on the effects of the osteokines FGF-23, IGF-1, RANKL and osteocalcin on muscle to explore whether these cytokines can be utilized to treat and prevent sarcopenia.

Moore AE, Kim E, Dulnoan, D,  Dolan AL, Voong, K, Ahmad I, et al.   Serum vitamin K 1 (phylloquinone) is associated with fracture risk and hip strength in post-menopausal osteoporosis: A cross-sectional study. Bone. 2020;141:115630.
Vitamin K may play a potential role in bone metabolism, although further evidence is needed. This study looked at optimal intake and skeletal effects.  elucidate these two issues, we investigated the association between circulating vitamin K1 (phylloquinone) concentrations with fracture risk, bone mineral density (BMD), hip geometry and plasma dephospho-uncarboxylated-Matrix Gla Protein (dp-ucMGP), an extra-hepatic vitamin K dependent protein (VKDP), in post-menopausal osteoporosis (PMO).  Our data suggest that the positive effect of vitamin K on fracture risk may be related to its effects on bone strength. Higher concentrations of serum vitamin K1 may be required for vitamin K's skeletal effects compared to coagulation. Further prospective or interventional studies are needed for confirmation and should include measures of bone quality.

Rahimi GRM, Bijeh N, Rashidlamir A.  Effects of exercise training on serum preptin, undercarboxylated osteocalcin and high molecular weight adiponectin in adults with metabolic syndrome.  Exp Physio.  2020 Mar;105(3):449-459.

Sato T, Inaba N, Yamashita T.  MK-4 and its effects on bone quality and strength.  Nutrients.  2020 Apr;12(4):965.
Vitamin K acts as a cofactor and is required for post-translational γ-carboxylation of vitamin K-dependent proteins (VKDP). The current recommended daily intake (RDI) of vitamin K in most countries has been established based on normal coagulation requirements. Vitamin K1 and menaquinone (MK)-4 has been shown to decrease osteocalcin (OC) γ-carboxylation at RDI levels. Among the several vitamin K homologs, only MK-7 (vitamin K2) can promote γ-carboxylation of extrahepatic VKDPs, OC, and the matrix Gla protein at a nutritional dose around RDI. MK-7 has higher efficacy due to its higher bioavailability and longer half-life than other vitamin K homologs. As vitamin K1, MK-4, and MK-7 have distinct bioactivities, their RDIs should be established based on their relative activities. MK-7 increases bone mineral density and promotes bone quality and strength. Collagen production, and thus, bone quality may be affected by MK-7 or MK-4 converted from MK-7. In this review, we comprehensively discuss the various properties of MK-7.

Shioi A, Morioka,T, Shoji T,  Emoto M. The inhibitory roles of vitamin K in progression of vascular calcification. Nutrients. 2020;12:583.
Vitamin K is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs) and may be implicated in cardiovascular disease (CVD). Vitamin K has been demonstrated to exert anti-inflammatory effects through antagonizing NF-κB signaling in both in vitro and in vivo studies, suggesting that vitamin K may prevent vascular calcification via anti-inflammatory mechanisms. Matrix Gla protein (MGP) is a major inhibitor of soft tissue calcification and contributes to preventing both intimal and medial vascular calcification. Vitamin K may also inhibit progression of vascular calcification by enhancing the activity of MGP through facilitating its γ-carboxylation. In support of this hypothesis, the pro-calcifying effects of warfarin, an antagonist of vitamin K, on arterial calcification have been demonstrated in several clinical studies. Among the inactive MGP forms, dephospho-uncarboxylated MGP (dp-ucMGP) may be regarded as the most useful biomarker of not only vitamin K deficiency, but also vascular calcification and CVD. There have been several studies showing the association of circulating levels of dp-ucMGP with vitamin K intake, vascular calcification, mortality, and CVD. However, additional larger prospective studies including randomized controlled trials are necessary to confirm the beneficial effects of vitamin K supplementation on CV health.

Sim M, Lewis JR Prince, RL, Levinger I, Brennan-Speranza TC, Palmer C, et al.  The effects of vitamin K-rich green leafy vegetables on bone metabolism: A 4-week randomised controlled trial in middle-aged and older individuals. Bone Rep. 2020;12:100274.

Smith C, Lin X, Scott D, Brennan-Speranza TC, Saedi AA, Moreno-Asso A, et al.  Uncovering the bone-muscle interaction and its implications for the health and function of older adults (The Welderly Project): protocol for a randomized control crossover trial. JMIR Res Protoc.  2021;10(4):e18777.
This study will provide novel insights into bone and muscle crosstalk in older adults, potentially identifying new clinical biomarkers and mechanistic targets for drug treatments for sarcopenia and other related musculoskeletal conditions.

Valenzuela P.L., Maffiuletti N.A., Joyner M.J., Lucia A., Lepers R. Lifelong Endurance Exercise as a Countermeasure Against Age-Related V˙O2max Decline: Physiological Overview and Insights from Masters Athletes. Sports Med2020;50:703–716.
Maximum oxygen consumption is not only an indicator of endurance performance, but also a strong predictor of cardiovascular disease and mortality. This physiological parameter is known to decrease with aging. In this narrative review, we summarize the evidence available from masters athletes about the role of lifelong endurance exercise on aging-related decline, with examples of the highest values reported in the scientific literature for athletes across different ages (e.g., 35 ml·kg-1·min-1 in a centenarian cyclist). These data suggest that a linear decrease in might be possible if physical exercise loads are kept consistently high through the entire life span, with values remaining higher than those of the general population across all ages. We also summarize the main physiological changes that occur with inactive aging at different system levels-pulmonary and cardiovascular function, blood O2 carrying capacity, skeletal muscle capillary density and oxidative capacity-and negatively influence and review how lifelong exercise can attenuate or even prevent most-but apparently not all (e.g., maximum heart rate decline)-of them. In summary, although aging seems to be invariably associated with a progressive decline in maintaining high levels of physical exercise along the life span slows the multi-systemic deterioration that is commonly observed in inactive individuals, thereby attenuating age-related decline.

Yang R, Pan J, Chen Y, Li Y, Wu J, Wang X.  Menaquinone-7 protects astrocytes by regulating mitochondrial function and inflammatory response under hypoxic conditions.  Eur Rev Med Pharmacol Sci. 2020;24:10181-93.

Carapeto PV, Aguayo-Mazzucato C.  Effects of exercise on cellular and tissue aging.  Aging (Albany NY).  2021;13(10):14522-14542.
The natural aging process is carried out by a progressive loss of homeostasis leading to a functional decline in cells and tissues. The accumulation of these changes stem from a multifactorial process on which both external (environmental and social) and internal (genetic and biological) risk factors contribute to the development of adult chronic diseases, including type 2 diabetes mellitus (T2D). Strategies that can slow cellular aging include changes in diet, lifestyle and drugs that modulate intracellular signaling. Exercise is a promising lifestyle intervention that has shown antiaging effects by extending lifespan and healthspan through decreasing the nine hallmarks of aging and age-associated inflammation. Herein, we review the effects of exercise to attenuate aging from a clinical to a cellular level, listing its effects upon various tissues and systems as well as its capacity to reverse many of the hallmarks of aging.

Crintea A, Dutu AG, Măsălar AL, Linga E, Constantin A-M, Crăciun A.  Vitamin K in sport activities:  a less considered benefit for athletic training.  Health, Sports & Rehab Med.  2021 Apr-Jun;22(2):127-132.
Vitamin K and its dependent proteins have important roles in several physiological or tumoral processes: bone mineralization, blood clotting, metabolism of blood vessel walls, tumoral angiogenesis and even cell growth and nervous system biochemistry (aspects of behavior and cognition). Vitamin K deficiency is associated with several diseases, including osteoporosis, vascular calcification and even depression. Through its involvement in cardiovascular and nervous system function, and bone metabolism, vitamin K supplementation could improve exercise capacity.

Dofferhoff ASM, Piscaer I, Schurgers LJ, Visser MPJ, van den Ouweland JMW, de Jong PA, et al.  Reduced yitamin K status as a potentially modifiable risk factor of severe coronavirus disease.  Clinical Infectious Diseases.  2021;73(12): e4039-e4046.
Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2–infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.

Fiorentini D, Cappadone C, Farruggia G, Prata C. Magnesium: Biochemistry, Nutrition, Detection, and Social Impact of Diseases Linked to Its Deficiency. Nutrients. 2021;13:1136.

Harper C, Gopalan V, Goh J.  Exercise rescues mitochondrial coupling in aged skeletal muscle:  a comparison of different modalities in preventing sarcopenia.  J Translational Med.  2021;19(71):
To an extent, lifelong exercise is efficacious in preserving the energetic properties of skeletal muscle and thus may delay the onset of sarcopenia. This review discusses the cellular and molecular changes in skeletal muscle mitochondria during the aging process and how different exercise modalities work to reverse these changes. A key factor that will be described is the efficiency of mitochondrial coupling—ATP production relative to O2 uptake in myocytes and how that efficiency is a main driver for age-associated decline in skeletal muscle function. With that, we postulate the most effective exercise modality and protocol for reversing the molecular hallmarks of skeletal muscle aging and staving off sarcopenia.

Hiam D, Landen S, Jacques M, Voisin S, Alvarez-Romero J, Byrnes E, Chubb P, et al.  Osteocalcin and its forms respond similarly to exercise in males and females.  Bone.  2021 Mar;144:115818.

Huertas JR, Casuso RA, Agustin PH, Cogliati S.  Corrigendum to “Stay Fit, Stay Young:  Mitochondria in Movement:  The Role of Exercise in the New Mitochondrial Paradigm”.  2021;Volume 2021 | Article ID 9274841 | https://doi.org/10.1155/2021/9274841

Kapoor K, Pi M, Nishimoto SK, Quarles LD, Baudry J, Smith JC.  The carboxylation status of osteocalcin has important consequences for its structure and dynamics.  Biochim Biophys Acta Gen Subj.  2021 Mar;1865(3):129809. 
The carboxylation status of Osteocalcin (Ocn) not only influences formation and structure in bones but also has important endocrine functions affecting energy metabolism and expenditure. In this study, the role of γ-carboxylation of the glutamate residues in the structure-dynamics-function relationship in Ocn is investigated. The carboxylation status of Ocn as well and its calcium coordination appear to have a direct influence on Ocn structure and dynamics, possibly leading to the known differences in Ocn biological function.

Memme JM, Erlich AT, Phukan G, Hood DA.  Exercise and mitochondrial health.  J Physiol. 2021;599(3):803-817.
To this point, exercise remains the most potent behavioural therapeutic approach for the improvement of mitochondrial health, not only in muscle, but potentially also in other tissues.

Oliveira AN, Richards BM, Slavin M, Hood DA.  Exercise is muscle mitochondrial medicine.  Exercise and Sport Sciences Reviews.  2021;49(2):67-76.
Exercise stimulates the biogenesis of mitochondria in muscle. Some literature supports the use of pharmaceuticals to enhance mitochondria as a substitute for exercise. We provide evidence that exercise rejuvenates mitochondrial function, thereby augmenting muscle health with age, in disease, and in the absence of cellular regulators. This illustrates the power of exercise to act as mitochondrial medicine in muscle.

Popa D-S, Bigman G, Rusu ME.  The role of vitamin K in humans:  Implication in aging and age-associated diseases.  Antioxidants.  2021;10:566.
As human life expectancy is rising, the incidence of age-associated diseases will also increase. Scientific evidence has revealed that healthy diets, including good fats, vitamins, minerals, or polyphenolics, could have antioxidant and anti-inflammatory activities, with antiaging effects. Recent studies demonstrated that vitamin K is a vital cofactor in activating several proteins, which act against age-related syndromes. Our review aimed to present the latest scientific evidence about vitamin K and its role in preventing age-associated diseases and/or improving the effectiveness of medical treatments in mature adults >50 years old

Rahimi GRM, Niyazi A, Alaee S.  The effect of exercise training on osteocalcin, adipocytokines, and insulin resistance:  a systematic review and meta-analysis of randomized controlled trials.  Osteo Int.  2021;32:213-224.
Recently, it has been reported that osteocalcin (OC), in particular its undercarboxylated (ucOC) form, is not only a bone remodeling marker but also an active hormone that intercedes glucose metabolism in humans. This study aimed to determine the impact of an exercise intervention on ucOC, adiponectin, leptin, and insulin resistance (measured by HOMA-IR). Our findings demonstrate that exercise-induced increases in ucOC are the probable cause of increased adiponectin. Additionally, increases in ucOC itself are probably due to changes in leptin levels and other factors, rather than its direct impact on bone and its osteoblastic activity. Further studies are required to clarify the mechanisms underlying the impact of exercise training on ucOC, adipocytokines, and insulin resistance.

Rantalainen T, Ridgers ND, Gao Y, Belavy DL, Haapala EA, Finni T.  Physical activity accumulation along the intensity spectrum differs between children and adults.  Eur J Applied Physio.  2021;121:2653-2571.

Detailed exploration of physical activity accumulation with fine grading along the intensity spectrum has indicated the potential pragmatic utility of such an approach. However, it is currently unclear what sorts of accumulation patterns along particular intensity bands are found in the children and adult populations. Therefore, we conducted a comparison of activity accumulation in specific intensity bands between four distinct populations: children, adults with sedentary lifestyles, habitual joggers, habitual marathon runners. Children accumulated more activity in normalized acceleration intensities compared to adults. Adult joggers/runners accumulated more activity in normalized acceleration intensities compared to the other groups.  The primary bulk of children’s free-living activities are of relatively low intensity not likely to provoke cardiometabolic improvement. These sorts of explorations could be used in informing intervention development aiming at optimizing healthy development. 

Smith C, Lin X, Scott D, et al. Uncovering the bone-muscle interaction and its implications for the health and function of older adults (the Wellderly project): protocol for a randomized controlled crossover trial. JMIR Res Protoc. 2021;10:e18777.

Smith C, Tacey A, Mesinovic J, Scott D, Lin X, Brennan-Speranza TC, et al.  The effects of acute exercise on bone turnover markers in middle-aged and older adults:  a systematic review.  Bone. 2021 Feb;143:115766.
Bone turnover is the cellular machinery responsible for bone integrity and strength and, in the clinical setting, it is assessed using bone turnover markers (BTMs). Acute exercise can induce mechanical stress on bone which is needed for bone remodelling, but to date, there are conflicting results in regards to the effects of varying mechanical stimuli on BTMs. This systematic review examines the effects of acute aerobic, resistance and impact exercises on BTMs in middle and older-aged adults and examines whether the responses are determined by the exercise mode, intensity, age and sex.  They found that acute exercise is an effective tool to modify BTMs, however, the response appears to be exercise modality-, intensity-, age- and sex-specific. There is further need for higher quality and larger RCTs in this area.

Sorriento D, Di Vaia E, Iaccrino G.  Physical exercise:  a novel tool to protect mitochondrial health.  Front Physiol.  2021;12:660068
In this review, we will deal with the effect of physical exercise on cardiac mitochondrial function tracing its ability to modulate specific steps in MQC both in physiologic and pathologic conditions.

Su X, Wang W, Fang C, Zhou J, Wang X, et al.  Vitamin K2 alleviates insulin resistance in skeletal muscle by improving mitochondrial biogenesis through moduling SIRT1 signaling.  Antioxid Redox Signal.  2021 Jan 10;34(2):99-117.

Touron J, Costes F, Coudeyre E, Perrault H, Richard R.  Aerobic metabolic adaptations in endurance eccentric exercise and training:  from whole body to mitochondria.  Front Physiol.  2021;11:596351.

Vitale JA, Sansoni V, Faraldi M, Messina C, Verdelli C, Lombardi G, et al.  Circulating carboxylated osteocalcin correlates with skeletal muscle mass and risk of fall in postmenopausal osteoporotic women.  Front Endocrinol. (Lausanne).  2021;12:669704.
Bone and skeletal muscle represent a single functional unit. We cross-sectionally investigated body composition, risk of fall and circulating osteocalcin (OC) isoforms in osteoporotic postmenopausal women to test the hypothesis of an involvement of OC in the bone-muscle crosstalk.  The data supported the relationship between OC and skeletal muscle mass and function in postmenopausal osteoporotic women. Serum cOC, but not uOC, emerges as mediator in the bone-muscle crosstalk. Circulating cOC and uOC levels may be differentially regulated in fractured and unfractured osteoporotic women, suggesting underlying differences in bone metabolism.

Zhou R, Guo Q, Xiao Y, Guo Q, Huang Y, Li C, et al.  Endocrine role of bone in the regulation of energy metabolism.  Bone Research.  2021;9(25): DOIhttps://doi.org/10.1038/s41413-021-00142-4
Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.

Alonso N, Meinitzer A, Fritz-Petrin E, Enko D, Herrmann.  Role of vitamin K in bone and muscle metabolism.  Calcified Tissue Int.  2022 Feb;112(2):178-196.
Vitamin K, a cofactor for the γ-glutamyl carboxylase enzyme, is required for the post-translational activation of osteocalcin and matrix Gla protein, which play a key role in bone and muscle homeostasis. In vivo and in vitro models for osteoporosis and sarcopenia suggest the vitamin K could exert a positive effect in both conditions. In bone, it increases osteoblastogenesis, whilst decreases osteoclast formation and function. In muscle, it is associated with increased satellite cell proliferation and migration and might play a role in energy metabolism. Observational trials suggest that high levels of vitamin K are associated with increased bone mineral density and reduced fracture risk.

Azuma K, Osuka Y, Kojima N, Sasai H, Kim H, Inoue S.  Association of vitamin K insufficiency as evaluated by serum undercarboxylated osteocalcin with frailty in community-dwelling older adults.  Front in Aging.  2022;3:865178.
Frailty is the state of having a reduced ability to recover from stress. Intervention in frailty is important for fulfilling healthy longevity. Vitamin K is a fat-soluble vitamin contained in vegetables and fermented foods. Although vitamin K is shown to be associated with several age-related diseases, studies on the association of vitamin K intake and frailty in the elderly population are limited. In the present study, a total of 800 community-dwelling older adults (mean age = 75.9) were recruited for a comprehensive geriatric health examination, including frailty evaluation based on the Japanese version of the Cardiovascular Health Study criteria. Our findings demonstrated the association between vitamin K insufficiency and frailty in the elderly population. Our analysis also suggests that vitamin K insufficiency could be associated with selected components of frailty.

Berkner KL, Runge KW.  Vitamin K-dependent protein activation:  Normal Gamma-Glutamyl Carboxylation and Disruption in Disease.  Int J Mol Sci.  2022 May;23(10):5759.
The review covers the roles of VKD proteins, how they become activated, and how disruption of carboxylation can lead to disease. VKD proteins contain clusters of Gla residues that form a calcium-binding module important for activity, and carboxylase processivity allows the generation of multiple Glas. The review discusses how impaired carboxylase processivity results in the pseudoxanthoma elasticum-like disease.

Brancaccio M, Mennitti C, Cesaro A, Fimiani F, Vano M, Gargiulo B, et al.  The biological role of vitamins in athletes muscle, heart and microbiota.  Int J Environ Res Public Health.  2022;19:1249.
Physical activity, combined with adequate nutrition, is considered a protective factor against cardiovascular disease, musculoskeletal disorders, and intestinal dysbiosis. Achieving optimal performance requires a significantly high energy expenditure, which must be correctly supplied to avoid the occurrence of diseases such as muscle injuries, oxidative stress, and heart pathologies, and a decrease in physical performance during competition. Moreover, in sports activities, the replenishment of water, vitamins, and minerals consumed during training is essential for safeguarding athletes’ health. Vitamins are introduced to the diet because the human body is unable to produce these micronutrients. The aim of this review is to highlight the fundamental role of vitamin supplementation in physical activity. Above all, we focus on the roles of vitamins A, B6, D, E, and K in the prevention and treatment of cardiovascular disorders, muscle injuries, and regulation of the microbiome.

Burtscher J, Strasser B, Burtscher, Millet GP.  The impact of training on the loss of cardiorespiratory fitness in aging masters endurance athletes. Int J Environ Res Public Health.  2022;19:11050.
Elite masters endurance athletes are considered models of optimal healthy aging due to the maintenance of high cardiorespiratory fitness (CRF) until old age. Whereas a drop in VO2max in masters athletes has been broadly investigated, the modifying impact of training still remains a matter of debate. Longitudinal observations in masters endurance athletes demonstrated VO2max declines between −5% and −46% per decade that were closely related to changes in training volume. Here, using regression analyses, we show that 54% and 39% of the variance in observed VO2max decline in male and female athletes, respectively is explained by changes in training volume. An almost linear VO2max decrease was observed in studies on young and older athletes, as well as non-athletes, starting a few days after training cessation, with a decline of as much as −20% after 12 weeks. Besides a decline in stroke volume and cardiac output, training cessation was accompanied by considerable reductions in citrate synthase and succinate dehydrogenase activity (reduction in mitochondrial content and oxidative capacity). This reduction could largely be rescued within similar time periods of training (re)uptake. It is evident that training reduction or cessation leads to a considerably accelerated VO2max drop, as compared to the gradual aging-related VO2max decline, which can rapidly nullify many of the benefits of preceding long-term training efforts.

Jadhav N , Ajgaonkar S , Saha P, Gurav P, Pandey A, Basudkar V, et al.  Molecular pathways and roles for vitamin K2‐7 as a health‐beneficial nutraceutical: Challenges and opportunitiesFrontiers in Pharmacology. 2022;13:896920.

Komori T.  Whole aspects of Runx2 functions in skeletal development.  Int J Mol Sci.  2022 May 21;23(1):5776.

Lavin KM, Coen PM, Baptista LC, Bell MB, Drummer D, Harper SA, et al.  State of knowledge on molecular adaptations to exercise in humans:  historical perspectives and future directions.  Compr Physiol. 2022 Mar 9;12(2):3193-3279.

Lee S, Kim J-S, Park K-S, Baek K-@, Yoo J-II.  Daily walking accompanied with intermittent resistance exercise prevents osteosarcopenia:  a large cohort study.  J Bone Metab.  2022 Nov;29(4):255-263.
This study aimed to analyze the effects of walking and resistance exercises on bone structure, bone mineral density (BMD), and skeletal muscle mass. We used data from the fourth Korean National Health and Nutrition Examination Survey (KNHANES).They found that when  resistance exercise and walking are combined, bone loss and muscle loss are prevented maintaining cortical thickness in the elderly. Walking for more than 5 days a week and resistance exercise for more than 2 days a week will help to maintain the skeletal muscle as well as the cortex around the femur neck, thus helping to prevent fragility fractures in older individuals.

Lithgow H, Johnston L, Ho FK, Celis-Morales C, Cobley J, Raastad T, et al.  Protocol for a randomized controlled trial to investigate the effects of vitamin K2 on recovery from muscle-damaging resistance exercise in young and older adults – the TAKEOVER study.  Trials.  2022;23:1026.
Regular participation in resistance exercise is known to have broad-ranging health benefits and for this reason is prominent in the current physical activity guidelines. Recovery after such exercise is important for several populations across the age range and nutritional strategies to enhance recovery and modulate post-exercise physiological processes are widely studied, yet effective strategies remain elusive. Vitamin K2 supplementation has emerged as a potential candidate, and the aim of the current study, therefore, is to test the hypothesis that vitamin K2 supplementation can accelerate recovery, via modulation of the underlying physiological processes, following a bout of resistance exercise in young and older adults.

Ma M-L, Ma Z-J, He Y-L, Sun H, Yang B, Ruan B-J, et al.  Efficacy of vitamin K2 in the prevention and treatment of postmenopausal osteoporosis: A systematic review and meta-analysis of randomized controlled trials.  2022 Aug 11;10:979649.
The results of this meta-analysis seem to indicate that VK2 supplementation has a positive effect on the maintenance and improvement of BMD LS in postmenopausal women, and it can also reduce the fracture incidence, serum uc-OC levels and the ratio of uc-OC to cOC. In conclusion, VK2 can indirectly promote bone mineralization and increase bone strength.

Mahatme S, Vaishali K, Nites K, Rao V, Rakesh KK, Sinha MK.  Impact of high-intensity interval training on cardio-metabolic health outcomes and mitochondrial function in older adults:  a review.  Med Pharm Rep.  2022 Apr;95(2):11-130.
Exercise being a potent stimulator of mitochondrial biogenesis, there is a need to investigate the effects of high-intensity interval training (HIIT) among older adults. This review explores and summarizes the impact of HIIT on mitochondria and various cardio-metabolic health outcomes among older adults, healthy and with comorbid conditions. Twenty-one studies that met the inclusion criteria are included in this review. HIIT is an innovative therapeutic modality in preserving mitochondrial quality with age and serves to be a viable, safe, and beneficial exercise alternative in both ill and healthy older adults.

Sim M, Strydom A, Blekkenhorst L, Bondonno NP, McCormick R, Lim WH et al.  Dietary Vitamin K1 intake is associated with lower long-term fracture-related hospitalization risk: the Perth longitudinal study of ageing women.  Food & Func.  2022;13:10642-10650.
This study examined the association between dietary Vitamin K1 intake with fracture-related hospitalizations over 14.5 years in community-dwelling older Australian women (n = 1373, ≥70 years). Over 14.5 years, any fracture and hip fracture related hospitalizations were captured using linked health data. Plasma Vitamin D status (25OHD) and the ratio of undercarboxylated osteocalcin (ucOC) to total osteocalcin (tOC) from serum was assessed at baseline. Compared to women with the lowest Vitamin K1 intake, women with the highest Vitamin K1 intake had lower hazards for any fracture, and hip fracture-related hospitalization independent of 25OHD levels, as part of multivariable-adjusted analysis. For hip fractures, a similar relationship was apparent. Higher dietary Vitamin K1 is associated with lower long-term risk for any fracture- and hip fracture-related hospitalizations in community-dwelling older women.

Su X, Zhou J, Wang W, Yin C, Wang F.  VK2 regulates slow-twitch muscle fibers expression and mitochondrial function via SIRT1/SIRT3 signaling.  Nutrition. 2022 Jan;93:111412.
Naturally occurring VK2 increases slow-twitch fibers by improving mitochondrial function and decreasing non-esterified fatty acid levels via partially SIRT1/SIRT3 signaling pathway. These data have potential importance for the therapy for a number of muscular and neuromuscular diseases in humans.. 

Tang H, Zheng Z, Wang, Wang L, Zhao G, Wang P.  Vitamin K2 modules mitochondrial dysfunction induced by 6-Hydroxydopamine in SH-SY5Y cells via mitochondrial quality-control loop.  Nutrients.  2022;14:1504.
Vitamin K2, a natural fat-soluble vitamin, is a potent neuroprotective molecule, owing to its antioxidant effect, but its mechanism has not been fully elucidated. Therefore, we stimulated SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) in a proper dose-dependent manner, followed by a treatment of vitamin K2. In the presence of 6-OHDA, cell viability was reduced, the mitochondrial membrane potential was decreased, and the accumulation of reactive oxygen species (ROS) was increased. Moreover, the treatment of 6-OHDA promoted mitochondria-mediated apoptosis and abnormal mitochondrial fission and fusion. However, vitamin K2 significantly suppressed 6-OHDA-induced changes. Vitamin K2 played a significant part in apoptosis by upregulating and downregulating Bcl-2 and Bax protein expressions, respectively, which inhibited mitochondrial depolarization, and ROS accumulation to maintain mitochondrial structure and functional stabilities. Additionally, vitamin K2 significantly inhibited the 6-OHDA-induced downregulation of the MFN1/2 level and upregulation of the DRP1 level, respectively, and this enabled cells to maintain the dynamic balance of mitochondrial fusion and fission. Furthermore, vitamin K2 treatments downregulated the expression level of p62 and upregulated the expression level of LC3A in 6-OHDA-treated cells via the PINK1/Parkin signaling pathway, thereby promoting mitophagy. Moreover, it induced mitochondrial biogenesis in 6-OHDA damaged cells by promoting the expression of PGC-1α, NRF1, and TFAM. These indicated that vitamin K2 can release mitochondrial damage, and that this effect is related to the participation of vitamin K2 in the regulation of the mitochondrial quality-control loop, through the maintenance of the mitochondrial quality-control system, and repair mitochondrial dysfunction, thereby alleviating neuronal cell death mediated by mitochondrial damage.

Vidula MK, Akers S, Ansari BA, Kim J, Kumas AA, Tamvada D, et al.  Increased dephospho-uncarboxylated Matrix Gla-protein is associated with lower axial skeletal muscle mass in patients with hypertension.  Am J Hypertens.  2022 May 10;35(5):393-396.
They examined the association of vitamin K2 deficiency and dpucMGP with skeletal muscle mass in patients with hypertension.  They found an inverse relationship between dpucMGP levels and axial muscle mass, with progressively rising dpucMGP levels correlating with decreasing axial muscle mass. In hypertensive adults, dpucMGP is independently associated with lower axial muscle mass, in addition to increased large artery stiffness. Further studies are required to investigate the role of vitamin K supplementation in this population.

Wang H, Li L, Zhang N, Ma Y.  Vitamin K2 improves osteogenic differentiation by inhibiting stat1 via the Bcl‐6 and IL‐6/JAK in C3H10 T1/2 Clone 8 cellsNutrients.  2022;14(14):2934. 10.3390/nu14142934

Xu D, Yang A, Ren R, Shan Z, Li YM, Tan J.  Vitamin K2 as a potential therapeutic candicate for the prevention of muscle cramps in hemodialysis patients:  A prospective multicenter, randomized, controlled, crossover pilot trial.  Nutrition.  2022 May;97:111608.
Muscle cramps occur in 33% to 78% of patients with dialysis. The etiology of muscle cramps is poorly understood, and no clear evidence-based prevention or treatment strategies exist. Improved interventions are urgently needed. The aim of this study was to investigate the effect of vitamin K2 in reducing the frequency and severity of muscle cramps in hemodialysis (HD) patients. Vitamin K2 reduced the frequency, duration, and severity of muscle cramps in HD patients (all P < 0.05). The frequency, duration, and severity of muscle cramps in HD patients increased again after crossing over to the placebo. There were no serious adverse events. One patient experienced gastrointestinal discomfort when taking vitamin K2.This pilot trial demonstrated that vitamin K2 supplementation could decrease the frequency, duration, and severity of muscle cramps in HD patients.

Egan B, Sharples AP. Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise trainingPhysiol Rev. 2023 Jul 1;103(3):2057-2170.

Furrer R, Hawley JA, Handschin.  The molecular athlete:  exercise physiology from mechanisms to medals.  Physiol  Rev.  2023 Jul 1;103(3):1693-1787.
Collectively, we provide a comprehensive overview of skeletal muscle plasticity in response to different modes of exercise and how such adaptations translate from “molecules to medals.”

Jesperson T, Kampmann FB, Dantoft TM,  Jørgensen  NR, Kårhus LL, Madsen F, Linneberg A, Thysen SM.  The association of vitamin K status with lung function and disease in a general population.  ERJ Open Res.2023 Sep;9(5): 00208-2023.
Lower vitamin K status was associated with lower lung function in a cross-sectional general population study. Individuals with lower vitamin K status were more likely to report chronic obstructive lung disease, wheezing, and asthma. Matrix Gla Protein (MGP) is an inhibitor of lung tissue calcification. Plasma levels of dephosphorylated-uncarboxylated MGP (dp-ucMGP) is a biomarker of vitamin K status. The present study assessed whether lower vitamin K status (reflected by higher dp-ucMGP) was associated with lung function and lung disease/symptoms.  A general population sample of 4,092 individuals, aged 24 to 77 years, underwent a health examination including questionnaires, spirometry, and measurements of plasma dp-ucMGP. They found that lower vitamin K status was associated with lower ventilatory capacity (lower FEV1 and FVC), and with higher risk of self-reported asthma, COPD, and wheezing. Vitamin K status was not associated with airflow obstruction (FEV1/FVC-ratio).  

Yan Q, Zhang T, O’Connor C, Barlow JW, Walsh J, Scalabrino G, et al.  The biological responses of vitamin K:  A comprehensive review.  Food Sci Nutro.  2023 Apr;11(4):1634-56.
Vitamin K1 (VitK1) and Vitamin K2 (VitK2), two important naturally occurring micronutrients in the VitK family, found, respectively, in green leafy plants and algae (VitK1) and animal and fermented foods (VitK2). The present review explores the multiple biological functions of VitK2 from recently published in vitro and in vivo studies, including promotion of osteogenesis, prevention of calcification, relief of menopausal symptoms, enhancement of mitochondrial energy release, hepato‐ and neuro‐protective effects, and possible use in treatment of coronavirus disease. The mechanisms of action associated with these biological effects are also explored. Overall, the findings presented here suggest that VitK, especially VitK2, is an important nutrient family for the normal functioning of human health. It acts on almost all major body systems and directly or indirectly participates in and regulates hundreds of physiological or pathological processes.

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