Myokines

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The term myokine refers to cytokines which are secreted by muscle cells. Cytokines are a diverse group of small proteins or proteoglycans. These intercellular communication molecules fulfill very diverse roles in regulation of cellular expression and differentiation whose systemic effects occur at mere picomolar concentrations. Of particular interest are their effects in tissue regeneration and repair, maintenance of healthy bodily functioning, immunomodulation and embryogenesis.

In 2003, Dr. Bente Klarlund Pedersen et al. suggested that cytokines or other peptides that are produced, expressed and released by muscle fibres and exert endocrine effects should be classified as myokines.

Myostatin was the first myokine identified. Its discovery occurred in Se-Jin Lee’s laboratory at Johns Hopkins University in 1997. Both aerobic exercise and strength training in humans and animals attenuate myostatin expression and myostatin inactivation seems to potentiate the beneficial effects of endurance exercise on metabolism.

While myostatin was the first muscle-derived peptide to fulfill the criteria for a myokine, the gp130 receptor cytokine IL-6 (Interleukin 6) was the first myokine that was found to be secreted into the blood stream in response to muscle contractions. Aerobic exercise provokes a systemic cytokine response, including, for example, IL-6, IL-1 receptor antagonist (IL-1ra), and IL-10 (Interleukin 10). IL-6 was serendipitously discovered as a myokine because of 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. It has been consistently demonstrated that the plasma concentration of IL-6 increases during muscular 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.

IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage. However, it has become evident that eccentric exercise is not associated with a larger increase in plasma IL-6 than exercise involving concentric “nondamaging” muscle contractions. This finding clearly demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.

IL-6, among an increasing number of other recently-identified myokines, thus 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 is seen as having a beneficial impact on health and bodily functioning in most circumstances. 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."

The emerging understanding of skeletal muscle as a secretory organ, and of myokines as mediators of physical fitness through the practice of regular physical exercise (including in particular strength training and aerobic exercise), as well as new awareness of the anti-inflammatory and thus disease prevention aspects of exercise, is thus transforming our broad understanding of the field of health promotion.

In a 2012 overview, Pedersen and Febbraio presented the following in an article abstract: "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. However, 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."

The authors concluded: "In summary, physical inactivity and muscle disuse lead to loss of muscle mass and accumulation of visceral adipose tissue and consequently to the activation of a network of inflammatory pathways, which promote development of insulin resistance, atherosclerosis, neurodegeneration and tumour growth and, thereby, promote the development of a cluster of chronic diseases. By contrast, the finding that muscles produce and release myokines provides a molecular basis for understanding how physical activity could protect against premature mortality.... Given that muscle is the largest organ in the body, the identification of the muscle secretome could set a new agenda for the scientific community. To view skeletal muscle as a secretory organ provides a conceptual basis for understanding how muscles communicate with other organs such as adipose tissue, liver, pancreas, bone and brain. Physical inactivity or muscle disuse potentially leads to an altered or impaired myokine response and/or resistance to the effects of myokines, which explains why lack of physical activity increases the risk of a whole network of diseases, including cardiovascular diseases, T2DM (Type 2 Diabetes Mellitus), cancer and osteoporosis."

In 2013, Dr. Pedersen summarized her research findings on myokines as follows: "Skeletal muscle is the largest organ in the body. Skeletal muscles are primarily characterized by their mechanical activity required for posture, movement, and breathing, which depends on muscle fiber contractions. However, skeletal muscle is not just a component in our locomotor system. Recent evidence has identified skeletal muscle as a secretory organ. We have suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert either autocrine, paracrine, or endocrine effects should be classified as 'myokines.' The muscle secretome consists of several hundred secreted peptides. This finding 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. In addition, several myokines exert their effects within the muscle itself. Many proteins produced by skeletal muscle are dependent upon contraction. Therefore, it is likely that myokines may contribute in the mediation of the health benefits of exercise.

All of the publications of the Danish Centre of Inflammation and Metabolism are accessible through this link: http://www.inflammation-metabolism.dk/index.php?pageid=21

Dr. Pedersen presented a talk at the TED conference on September 18, 2012. This 12-minute presentation highlights her primary research findings in a brief overview format for a general audience.