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 muscle cells (myocytes) in response to muscular contractions. They have autocrine, paracrine and/or endocrine effects; their systemic effects occur at picomolar concentrations. A myokine is one of several hundred cytokines or other small proteins (~5–20 kDa) and proteoglycan peptides that are produced and released by muscle cells (myocytes) 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 reflect 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. 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. 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.' 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. 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. 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.' Both aerobic exercise and strength training (resistance exercise) attenuate myostatin expression, and myostatin inactivation potentiates the beneficial effects of endurance exercise on metabolism.