myokine myokine a myokine is one of several hundred cytokines or other small proteins (~5–20 kda) and proteoglycan peptides that are produced and released by skeletal muscle cells (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. history the definition and use of the term myokine first occurred in 2003. in 2008, the first myokine, myostatin, was identified. the gp130 receptor cytokine il-6 (interleukin 6) was the first myokine found to be secreted into the blood stream in response to muscle contractions. functions in repetitive skeletal muscle contractions there is an emerging understanding of skeletal muscle as a secretory organ, and of myokines as mediators of physical fitness through the practice of regular physical exercise (aerobic exercise and strength training), as well as new awareness of the anti-inflammatory and thus disease prevention aspects of exercise. different muscle fiber types – slow twitch muscle fibers, oxidative muscle fibers, intermediate twitch muscle fibers, and fast twitch muscle fibers – release different clusters of myokines during contraction. this implies that variation of exercise types, particularly aerobic training/endurance training and muscle contraction against resistance (strength training) may offer differing myokine-induced benefits. "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 pancreatic islets. 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." in brain functions related to neuroplasticity, memory, sleep and mood physical exercise rapidly triggers substantial changes at the organismal level, including the secretion of myokines and metabolites by muscle cells. for instance, aerobic exercise in humans leads to significant structural alterations in the brain, while wheel-running in rodents promotes neurogenesis and improves synaptic transmission in particular in the hippocampus. moreover, physical exercise triggers histone modifications and protein synthesis which ultimately positively influence mood and cognitive abilities. notably, regular exercise is somewhat associated with a better sleep quality, which could be mediated by the muscle secretome. in regulating heart architecture heart muscle is subject to two kinds of stress: physiologic stress, i.e. exercise; and pathologic stress, i.e. disease related. likewise, the heart has two potential responses to either stress: cardiac hypertrophy, which is a normal, physiologic, adaptive growth; or cardiac remodeling, which is an abnormal, pathologic, maladaptive growth. upon being subjected to either stress, the heart "chooses" to turn on one of the responses and turn off the other. if it has chosen the abnormal path, i.e. remodeling, exercise can reverse this choice by turning off remodeling and turning on hypertrophy. the mechanism for reversing this choice is the microrna mir-222 in cardiac muscle cells, which exercise up-regulates via unknown myokines. mir-222 represses genes involved in fibrosis and cell-cycle control. in immunomodulation immunomodulation and immunoregulation were a particular focus of early myokine research, as, according to dr. bente klarlund pedersen and her colleagues, "the interactions between exercise and the immune system provided a unique opportunity to evaluate the role of underlying endocrine and cytokine mechanisms." 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. specific myokines myostatin both aerobic exercise and strength training (resistance exercise) attenuate myostatin expression, and myostatin inactivation potentiates the beneficial effects of endurance exercise on metabolism. interleukins aerobic exercise provokes a systemic cytokine response, including, for example, il-6, il-1 receptor antagonist (il-1ra), and il-10 (interleukin 10) and the concentrations of chemokines, il-8, macrophage inflammatory protein α (mip-1α), mip-1β, and mcp-1 rise after vigorous exercise. il-6 was identified as a myokine based on the observation that it increased in an exponential fashion proportional to the length of exercise and the amount of muscle mass engaged in the exercise. this increase is followed by the appearance of il-1ra and the anti-inflammatory cytokine il-10. in general, the cytokine response to exercise and sepsis differs with regard to tnf-α. thus, the cytokine response to exercise is not preceded by an increase in plasma-tnf-α. following exercise, the basal plasma il-6 concentration may increase up to 100-fold, but less dramatic increases are more frequent. the exercise-induced increase of plasma il-6 occurs in an exponential manner and the peak il-6 level is reached at the end of the exercise or shortly thereafter. it is the combination of mode, intensity, and duration of the exercise that determines the magnitude of the exercise-induced increase of plasma il-6. 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." interleukin 15 interleukin-15 stimulates fat oxidation, glucose uptake, mitochondrial biogenesis and myogenesis in skeletal muscle and adipose tissue. in humans, basal concentrations of il-15 and its alpha receptor (il-15rα) in blood have been inversely associated with physical inactivity and fat mass, particularly trunk fat mass. moreover, in response to a single session of resistance exercise the il-15/il-15rα complex has been related to myofibrillar protein synthesis (hypertrophy). brain-derived neurotrophic factor