For a long time the SM was considered to be an organ solely restricted to locomotion, protein storage and heat generation. However, it is now known that the SM has a high capacity for gene expression and repression through intracellular signals which become particularly present during exercise. The second messengers identified include: the increase in intracellular calcium, the depletion of adenosine triphosphate (ATP), Nicotinamide adenine dinucleotide (NAD) and the increase in reactive oxygen species (ROS) in addition to extracellular signals such as extracellular oxygen pressure, endocrine signalling and mechanical stimuli.10

The main regulator of gene activity with regard to exercise is made up of the peroxisome proliferation-activated receptor-gamma coactivator 1α (PCG-1α),11 a protein which is necessary for gene transcription and which induces, among other functions, adaptive SM processes. Some responses associated with PCG-1α are: the increase in the expression of insulin receptors, the uptake of fatty acids and glucose, glycogen storage and mitochondrial biogenesis.11

PCG-1α also promotes the synthesis of myokines with an endocrine effect on the SM itself and on fatty tissue organs,12 bone,13 brain,14 pancreas,15 intestine,16 and brown fat,17 among others. The term myokine was coined in 2003 by Dr. Bente Klarlund Pedersen in the muscle research centre in Copenhagen - Denmark18 and through the muscle secretoma study hundreds of substances have been found to be expressive in response to exercise.19 A graphic summary of the production of myokines through exercise is contained in Fig. 2.

Figure 2.

ATP=adenosine triphosphate, NAD=Nicotinamide Adenine Dinucleotide, ROS=Reactive Oxygen Species, HIF=hypoxia inducible factor, cAMP=cyclic cAMP, PCG-1α=peroxisome proliferation-activated receptor-gamma coactivator 1α, GLUT4=glucose transporter 4. IL-6=Interleukin 6, LIF=leukaemia inhibitor factor, IL-15=Interleukin 15, BDNF=brain-derived neurotrophic factor, FGF21=fibroblast growth factor 21.

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The most recent findings regarding the main myokines and their potential application are described below, both for the advocacy of physical exercise for health and for sports training.

Interleukin (IL-6), is a protein of 212 amino acids and a weight of de ∼26 kDa, produced by fatty tissue, the SM and different immune system cells.20 It is associated with physical exercise and its plasmatic concentration increases several times after it21 as a result of muscle contraction and changes in intracellular energy behaviour.22

The IL-6 (IL-6R) membrane receptor requires a pair of glycoproteins to act as co-receptors (gp130), to form the complex IL-6-IL6R-gp130 and to activate their intracellular action. Given that few cells express IL-6R, unlike the gp130 present in practically all cellular populations,23 lIL-6 requires a soluble receptor (sIL-6R)24 to attach itself to them all.

When soluble receptors are used the signalling pathway is called “trans”, and when membrane receptors are used the signalling pathway is called “classic”,25 with the classic being anti-inflammatory and the trans being inflammatory.26

During physical exercise the SM produces IL-6, but not sIL-6R, since the latter is produced by an enzymatic cleavage from other cells in the presence of inflammatory cytokines such as the tumour necrosis factor-alpha (TNF-α).27 In this way, IL-6, like myokine, only acts in cells which express IL-6R. On uniting with its receptor, the intracellular signalling involves Janus Kinases (JAK), which phosphorylate proteins responsible for the transduction signals and activators of transcription (STAT), which promote protein transcription in the nucleus.28 The JAK also phosphorylate kinase proteins activated by AMP (AMPK) and Phosphatidyl Inositol 3 Kinase (PI3K),29 enhancing uptake and use of energetic substrates, the increase in sensitivity to insulin and oxidation of fatty acids.30 In addition to this, the IL-6 plays a part in hypertrophy and myogenesis through stimuli generated on satellite cells.31

Furthermore, IL-6 increases lipolysis and sensitivity to insulin in fatty tissue,32 optimises the production of insulin in the pancreas33 and increases glycogenolysis and lipolysis in the liver.34 It has also been discovered that the sharp rise of IL-6 in the heart, limits cardiac lesions and has a cardio protective effect, in contrast to chronic elevation where there are deleterious effects.35

The sharp rise of plasmatic concentration of IL-6 also has an anti-inflammatory effect and regulates the acute inflammatory response. This occurs when the liberation of anti-inflammatory cytokines enables IL-1 (IL-1ra) and IL1040 receptor antagonists and inhibit the production of the tumour necrosis factor alpha (TNFα).36

Growing evidence of the beneficial effects of IL-6 are a contrast to the classical vision of its inflammatory effect. During exercise IL-6 may increase its baseline concentration up to 100 times, with the sharpest increase having a medium short life, unlike inflammation where the IL-6 increases in the company of other inflammatory cytokines such as TNF-α37 (Fig. 3).

Figure 3.

Endocrine and autocrine responses to Interleukin 6 (IL-6) and the leukaemia inhibitory factor (LIF), PI3K=Phosphatidyl Inositol 3 Kinase, AMPK=AMP activated protein kinase, JAK=Janus Kinase, STAT=Signal transduction and activators of transcription.

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The LIF is a 19.7 kDa protein made up of 181 amino acids associated with the differentiation of leukaemia myeloid cells and with stimulus for the formation of haematopoietic cells.38 LIF shares the co-receptor gp130 with IL-6, and therefore has a good proportion of inflammatory and anti-inflammatory effects. With regard to exercise, LIF is associated with muscle hypertrophy39 and with muscle hyperplasia.40 due to paracrine action on satellite cells. It has also recently been suggested that LIF increases glucose uptake by the MS41 in mice (Fig. 3).

IL15 is a cytokine of 12.9kDa, which was discovered in 1994 in T lymphocytes and which has usually been linked with inflammatory processes.42 However, IL15 is also produced by the SM in response to exercise (particularly in strength training),43 and IL-15 (IL15Rα) receptors have been found in the cells responsible for energy control: the rhabdomyocytes, adipocytes and hepatocytes.44

The intracellular signalling of IL15Rα is also associated with the JAK/STAT system, which explains the similarity existing in metabolic response with IL-6 and LIF.45 A major expression of IL-15 in the SM leads to greater uptake of glucose (seemingly due to the expression of GLUT4 receptors),46 greater uptake of fatty acids and an increase in the gene expression which promotes oxidative processes47 generating an additional antioxidant effect.48 Initially IL-15 was shown to be an activator of protein synthesis but recent evidence has focused not just on its anabolic action but on its effect at rhabdomyocytes metabolism regulation level.49

In fatty tissue IL-15 promotes lipolysis on producing greater mitochondrial activity50 and inhibiting the differentiation of preadipocytes.51 There is thus an inversely proportional relationship between the concentration of IL-15 in plasma and fatty tissue, particularly visceral.52 In brown fat, IL-15 increases the expression of uncoupling proteins, the transport of fatty acids and the thermogenic effect,53 which is an indication that IL-15 could generate interesting changes in body composition. However, the previously described effects are the results of experimentation in mice, and physiological responses in human beings are yet to be studied.54

IL-15 has recently been described as a major modulator of the immune system with an anti-inflammatory effect, on reducing the expression of TNF-α,55 with a potentially beneficial effect in illnesses such as obesity and diabetes mellitus type 2 (DM2).56

BDNF is a protein with a weight of 27kDa, produced in particular by the central nervous system, with a major role in neuronal development and in the processes of memory and learning.57 Low levels of BDNF have been found in neurodegenerative and metabolic diseases such as obesity, DM2 and cardiovascular disease.58

BDNF is attached to a kinase B receptor related to tropomyosin (TrkB), where it interacts with different second messengers including PI3K, and this to a large extent explains its metabolic and mitogenic functions.59 At present, BDNF is considered a myokine, produced during particularly aerobic physical exercise and under energetic stress conditions.60,61

Due to autocrine action, BDNF plays an important role in regeneration and probably in muscle adaptation secondary to exercise.62 Due to endocrine action, changes in plasmatic BDNF caused by physical exercise are related to effects in the brain cortex, optimising the execution of superior mental functions, particularly in older adults.63 In addition, BDNF generates greater oxidation of fats, a reduction in the size of fatty tissue, greater sensitivity to insulin and a reduction in appetite due to direct interaction on a hypothalamic level.64

FGF-21 belongs to a family of growth factors produced by several cells and with controversial physiological effects.65 It forms part of a superfamily of growth factors and its molecular weight ranges between 17 and 26kDa.64 FGF-21 is attached to a membrane receptor (FGFR1) and relies on an enzymatic cofactor called β-Klotho. The complex FGFR1/β-Klotho is found in the fatty tissue and the SM, and is intracellularly linked with the phosphorylation of STAT and other protein expression regulators such as the kinase proteins activated by mitogens (MAPK).66

FGF-21 is produced by the SM during physical exercise,67 and leads to enhanced muscle metabolic activity with greater oxidative capacity of glucose and fatty acids,68 in addition to a major antioxidant effect.69 However, its myokine effect is disputed since in conditions of non exercise and even in many pathologies it is possible to find that it has increased.

There are currently other myokines which are the object of investigation due to their potential metabolic effect. Myonectine is linked to exercise with the metabolism of fatty acids,70 Fibronectin type III (Irisin) has a potential effect on the formation of beige fat from white fat,71 Beta-amino-isobutyric acid (BAIBA) is able to reduce fatty tissue,72 the secreted protein acidic and rich in cysteine (SPARC or osteonectin) has an effect on the metabolism of carbohydrates73 and Musclin induces mitochondrial biogenesis.74

To guarantee sufficient, continuous support of substrates with which energy reserves may be replaced and tissue repair ensured, the SM generates myokines to promote hydrolysis of triglycerides in fatty tissue and a higher uptake of fatty acids by the SM, among which are found IL-6, IL-15, BDNF, FGF21 and BAIBA. In turn, these generate a reduction in size of adipocytes (particularly visceral), which has an interesting effect in relation to the effects of physical exercise on conditions such as obesity.75

Since SM also uses carbohydrates during exercise, several myokines (IL-6, LIF, IL-15, FGF-21, FNDC5, SPARC) also favour the expression of GLUT4 in SM through independent mechanisms of insulin, which reduces plasmatic concentrations in glucose during exercise and up to 24h after it. These effects reinforce the already well-known impact on the prevention and management of the different forms of Diabetes Mellitus.75

Since inflammation, like exercise, requires metabolic substrates, it is possible to understand how several myokines are related to the immune system and are involved in inflammatory processes.