A myokine is one of several hundred or other small (~5–20 kDa) and proteoglycan that are produced and released by Skeletal muscle (muscle fibers) in response to muscular contractions. They have autocrine, paracrine and/or endocrine effects; their systemic effects occur at picomolar concentrations.
Receptors for myokines are found on muscle, fat, liver, pancreas, bone, heart, immune, and brain cells. The location of these receptors reflects the fact that myokines have multiple functions. Foremost, they are involved in exercise-associated metabolic changes, as well as in the metabolic changes following training adaptation. They also participate in tissue regeneration and repair, maintenance of healthy bodily functioning, immunomodulation; and cell signaling, expression and differentiation.
"Some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and . Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1alpha-dependent myokine irisin, which drives brown fat-like development. 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."
Muscle has an impact on the trafficking and inflammation of lymphocytes and neutrophils. During exercise, both neutrophils and NK cells and other lymphocytes enter the blood. Long-duration, high-intensity exercise leads to a decrease in the number of lymphocytes, while the concentration of neutrophils increases through mechanisms including adrenaline and cortisol.Interleukin-6 has been shown to mediate the increase in Cortisol: IL-6 stimulates the production of cortisol and therefore induces leukocytosis and lymphocytopenia.
As studies have demonstrated IL-6 has pro-inflammatory functions when evaluated in regard to sepsis and obesity, it was initially hypothesized that the exercise-induced IL-6 response was related to muscle damage. However, a recent study suggests that eccentric exercise is not associated with a larger increase in plasma IL-6 than exercise involving concentric “nondamaging” muscle contractions. This finding supports the hypothesis that muscle damage is not required to provoke an increase in plasma IL-6 during exercise.
IL-6, among an increasing number of other recently identified myokines, remains an important topic of myokine research. It appears in muscle tissue and in the circulation during exercise at levels up to one hundred times basal rates, as noted, and may have a beneficial impact on health and bodily functioning with transient increases as P. Munoz-Canoves et al. write: "It appears consistently in the literature that IL-6, produced locally by different cell types, has a positive impact on the proliferative capacity of muscle stem cells. This physiological mechanism functions to provide enough muscle progenitors in situations that require a high number of these cells, such as during the processes of muscle regeneration and hypertrophic growth after an acute stimulus. IL-6 is also the founding member of the myokine family of muscle-produced cytokines. Indeed, muscle-produced IL-6 after repeated contractions also has important autocrine and paracrine benefits, acting as a myokine, in regulating energy metabolism, controlling, for example, metabolic functions and stimulating glucose production. It is important to note that these positive effects of IL-6 and other myokines are normally associated with its transient production and short-term action."
"Most recently, we have shown that BDNF appears to be a major player not only in central metabolic pathways but also as a regulator of metabolism in skeletal muscle. Hippocampal samples from Alzheimer’s disease donors show decreased BDNF expression and individuals with Alzheimer’s disease have low plasma levels of BDNF. Also, patients with major depression have lower levels of serum BDNF than normal control subjects. Other studies suggest that plasma BDNF is a biomarker of impaired memory and general cognitive function in ageing women and a low circulating BDNF level was recently shown to be an independent and robust biomarker of mortality risk in old women. Low levels of circulating BDNF are also found in obese individuals and those with type 2 diabetes. In addition, we have demonstrated that there is a cerebral output of BDNF and that this is inhibited during hyperglycaemic clamp conditions in humans. This last finding may explain the concomitant finding of low circulating levels of BDNF in individuals with type 2 diabetes, and the association between low plasma BDNF and the severity of insulin resistance.BDNF appears to play a role in both neurobiology and metabolism. Studies have demonstrated that physical exercise may increase circulating BDNF levels in humans. To identify whether the brain is a source of BDNF during exercise, eight volunteers rowed for 4 h while simultaneous blood samples were obtained from the radial artery and the internal jugular vein. To further identify the putative cerebral region(s) responsible for BDNF release, mouse brains were dissected and analysed for BDNF mRNA expression following treadmill exercise. In humans, a BDNF release from the brain was observed at rest and increased 2- to 3-fold during exercise. Both at rest and during exercise, the brain contributed 70–80% of the circulating BDNF, while this contribution decreased following 1 h of recovery. In mice, exercise induced a 3- to 5-fold increase in BDNF mRNA expression in the hippocampus and cortex, peaking 2 h after the termination of exercise. These results suggest that the brain is a major but not the sole contributor to circulating BDNF. Moreover, the importance of the cortex and hippocampus as sources of plasma BDNF becomes even more prominent in the response to exercise.”
With respect to studies of exercise and brain function, a 2010 report is of particular interest. Erickson et al. have shown that the volume of the anterior hippocampus increased by 2% in response to aerobic training in a randomized controlled trial with 120 older adults. The authors also summarize several previously-established research findings relating to exercise and brain function: (1) Aerobic exercise training increases grey and white matter volume in the prefrontal cortex of older adults and increases the functioning of key nodes in the executive control network. (2) Greater amounts of physical activity have been associated with sparing of prefrontal and temporal brain regions over a 9-y period, which reduces the risk for cognitive impairment. (3) Hippocampal and medial temporal lobe volumes are larger in higher-fit older adults (larger hippocampal volumes have been demonstrated to mediate improvements in spatial memory). (4) Exercise training increases cerebral blood volume and perfusion of the hippocampus.
Regarding the 2010 study, the authors conclude: "We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function."
However, exogenous irisin may aid in heightening energy expenditure, and thus in reducing obesity. Boström et al. reported on December 14, 2012: "Since the conservation of calories would likely provide an overall survival advantage for mammals, it appears paradoxical that exercise would stimulate the secretion of a polypeptide hormone that increases thermogenesis and energy expenditure. One explanation for the increased irisin expression with exercise in mouse and man may have evolved as a consequence of muscle contraction during shivering. Muscle secretion of a hormone that activates adipose thermogenesis during this process might provide a broader, more robust defense against hypothermia. The therapeutic potential of irisin is obvious. Exogenously administered irisin induces the browning of subcutaneous fat and thermogenesis, and it presumably could be prepared and delivered as an injectable polypeptide. Increased formation of brown or beige/brite fat has been shown to have anti-obesity, anti-diabetic effects in multiple murine models, and adult humans have significant deposits of UCP1-positive brown fat. (Our data show) that even relatively short treatments of obese mice with irisin improves glucose homeostasis and causes a small weight loss. Whether longer treatments with irisin and/or higher doses would cause more weight loss remains to be determined. The worldwide, explosive increase in obesity and diabetes strongly suggests exploring the clinical utility of irisin in these and related disorders. Another potentially important aspect of this work relates to other beneficial effects of exercise, especially in some diseases for which no effective treatments exist. The clinical data linking exercise with health benefits in many other diseases suggests that irisin could also have significant effects in these disorders."
While the murine findings reported by Boström et al. appear encouraging, other researchers have questioned whether irisin operates in a similar manner in humans. For example, Timmons et al. noted that over 1,000 genes are upregulated by exercise and examined how expression of FNDC5 was affected by exercise in ~200 humans. They found that it was upregulated only in highly active elderly humans, casting doubt on the conclusions of Boström et al. Further discussion of this issue can be found in .
Macrophages M2 stimulate satellite cells for proliferation and growth but M1 stimulates blood vessels and produces pro-inflammatory cytokines only M2 produces anti-inflammatory in muscles.
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