Skeletal muscle is endocrine organ

Muscle cells are able to release proteins and peptides that influence the functional activity of other tissues cells. These bioactive molecules were called myokines. The (main) factor of production of myokines is physical activity, the level of myokines depend significantly on the amount of muscle mass involved in the work. Myokines involved in intercellular communication are an important element in the homeostasis and adaptation of the organism to physical exercise. At the present we have many data that myokines may be a single functional system, which plays an important role in the mechanisms of organism adaptation to regular physical activity.

Key word: skeletal muscle, endocrine organ, myokine, IL-6, IL-8, IL-15.

Recently a new endocrine role of the skeletal muscle has been determined. Thus, it was suggested that cytokines and other peptides which are produced, expressed and released by muscle fibres have autocrine, paracrine and endocrine effect. These cytokines were called «myokines». In the result researchers have a new supposition that skeletal muscle interact with other organs such as adipose tissue, liver, pancreas, bones and brain. However, some myokines have effect only in skeletal muscle [8].

New data about skeletal muscle indicate that myokines play an important role in resolving acute metabolic changes during exercise and metabolic changes in adaptive post-training process [10]. Some of the positive effects in the result of regular physical exercise which is produced by myokines are: the increase of insulin sensitivity, glucose uptake and fatty acid oxidation in skeletal muscle. In addition, these molecules are involved in various short-term and long-term metabolic regulatory mechanisms in distant organs, for example, on adipose tissue [1]. Thus, myokines are a main element between skeletal muscles and other organs in and after training process. Consequently, further study of the influence and regulation of myokines is important.

Among myokines the most important and investigated are interleukin-6 (Il-6), Il-8, Il-15, Brain-Derived Neurotrophic Factor (BDNF) and Leukemia Inhibitory factor (LIF) [12].

One of the first cytokine which was proposed as myokine was IL-6. The first who suggest it was Pedersen in 2003 [9]. In 2000 it was discovered that the level of IL-6 is increased in plasma during physical exercise [14], further studies showed that IL-6 released from skeletal muscle and played an important role in metabolic processes [8]. It was later found that production of IL-6 increases during the training process when the level of glycogen is reduced. It can be explained as the probable reaction of the muscle-specific metabolic process [6]. IL-6 is produced by type I and type II fibers in response to muscle contraction [6,11]. In skeletal muscle IL-6 activates AMPK (AMP-kinase) and/or PI3-kinase, increasing the consumption of glucose and fat oxidation. Then IL-6 is released into the bloodstream, it comes to the liver, where it promotes the production of glucose during exercise and in adipose tissue increases lipolysis [4]. As a result, the effects of IL-6 produced by skeletal muscle increase the availability of energy substrates for muscle contraction [12].

Further evidence supports the role of IL-6 in metabolism of glucose in the liver. It was shown that this myokine inhibits activity of glycogen-synthase and activate glycogen-phosphorilase [5]. Also a possible increase of basal and insulin-stimulated glucose uptake occurs through an increase the translocation of GLUT4 from the intracellular part of the plasmatic membrane muscle cells [2], which indicate an important role of this myokine and skeletal muscle in glucose homeostasis. Consequently, the appearance of IL-6 in the blood flow is the result of the achievements of skeletal muscles, in order to maintain glucose homeostasis during periods of metabolic change or under insulin stimulus [2].

IL-6 is proinflammatory cytokines. One of its function is release of IL-6 in response to infectious agent. However, contractile-induced production of IL-6 by skeletal muscles occurs in the absence of other inflammatory mediators, such as IL-10 and TNF-a. This indicates that the production of IL-6 in response to physical exercise is not an inflammatory process. On the contrary, physical exercise increases the level of anti-inflammatory cytokines, such as IL-1ra, IL -10 and soluble TNF-R is a natural inhibitor of TNF-a [8].

During exercise IL-6 may have anti-inflammatory effects because data indicate that this myokine is able to suppress the synthesis of IL-1 and TNF-a [13] and stimulate the production of IL-1ra and IL-10 [15].

Another cytokine that can be classified as myokine is IL-15. IL-15 is secreted by various cell types such as macrophages, neutrophils and skeletal muscle cells. IL-15 is induced in immune cells by endotoxin and in muscle cells by physical exercises. Transcription of IL-15 is done by transcription factor NF-κB. IL-15 binding with its receptor which composed of three different subunits (α, β, and γ) activates the JAK/STAT, PI3K/Akt, IKK/NF-κB and JNK/AP1 signalling pathways in cells.

IL-15 inhibits lipogenesis, activates brown fat, and increases insulin sensitivity through weight loss and energy consumption. In human circulating IL-15 is negatively associated with body weight.

In the immune system IL-15 stimulates the proliferation and differentiation of T-cells, NK-cells, monocytes and neutrophils. In curing obesity effects of IL-15, T-cells and NK-cells are not required, but the ones necessary are leptin receptors [21].

In conclusion we can say that the proinflammatory cytokine IL-15 can increase energy consumption for protection of the body from obesity and diabetes mellitus type 2. However, the mechanism of action of IL-15 is not fully studied [17].

ThenextmyokineisIL-8. Il-8 is a known chemokine for neutrophils but it also acts as an angiogenic factor. Plasmatic level of IL-8 increases in response to physical exercise involving eccentric contractions of muscles [18] but plasmatic levels of IL-8 do not increases in response to concentric exercise [19].

It is discovered that IL-8 produced by skeletal muscle acts locally and has an autocrine or paracrine effect [19]. It is unlikely that IL-8 produced by muscles will work as a chemoattractant for neutrophils and macrophages, because during concentric exercise the accumulation of neutrophils or macrophages in skeletal muscle is very small or absent entirely. However, the most possible function of IL-8 produced by the muscle is the stimulation of angiogenesis. IL-8 participate in signalling pathway which provides angiogenic response in endothelial cells, increases proliferation and survival of endothelial cells. Therefore, expression of IL-8 correlates with angiogenesis and regenerative processes [20].

The conclusion is that high local emission of IL-8 in contractile muscle does not lead to the increase of IL-8 in plasma, suggests that the muscle produced IL-8 has no systemic effects. However, it is likely that IL-8 produced by myofibrils exerts its action locally and plays a role in exercise-induced angiogenesis [21].

Physical activity of different intensities leads to a large number of biochemical, molecular and genetic mechanisms underlying the adaptive responses of the organism on the physiological stress. Processes of adaptation of organism to physical exercise of different character are associated with changes in nervous and humoral regulation, adequate restructuring of the central and peripheral hemodynamics, etc. Thus, physical activity has a direct effect on skeletal muscles and systemic effects on the body which is largely mediated by products of myokines. As a consequence, myokines considered one of the most important factors in maintaining homeostasis and muscle adaptation to physical activity [7].

In conclusion, we can note that the influence of myokines on the organs and systems of the body are still not fully investigated.

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