Rev Bras Fisiol Exerc 2020;19(5):421-34

doi: 10.33233/rbfex.v19i5.4630

REVIEW

Responses of myokines concentrations from exercise stimulus: a systematic review

Respostas das concentrações de miocinas a partir do estímulo do exercício físico: uma revisão sistemática

 

Leandro Paim da Cruz Carvalho1, Matheus Borges da Cruz Gomes2, Ícaro Cerqueira da Silva Oliveira¹, Pedro Henrique Silva Santos3, Ariel Custódio de Oliveira II1, Lorena Mariel González Vitavar4, Heitor Barbosa Alves2

 

1Universidade Federal do Vale do São Francisco, Petrolina, PE, Brazil

2Universidade Estadual de Feira de Santana, Feira de Santana, BA, Brazil

3Fundação Estatal de Saúde da Família/Fundação Oswaldo Cruz (FESF/FioCruz), Salvador, BA, Brazil

4Facultad de Ciencias de la Salud – Universidad Adventista del Plata, Libertador San Martín, Entre Ríos, Argentina

 

Received on: September 10, 2020; Accepted on: September 16, 2020.

Corresponding author: Leandro Paim da Cruz Carvalho, Rua Santo Amaro, 133 Chácara São Cosme, Feira de Santana BA

 

Leandro Paim da Cruz Carvalho: leandroopaim@hotmail.com

Matheus Borges da Cruz Gomes: matheus_gomes97@outlook.com

Ícaro Cerqueira da Silva Oliveira: icaroocerqueira@hotmail.com

Pedro Henrique Silva Santos: pedrohss92@yahoo.com.br

Ariel Custódio de Oliveira II: arielcohab@gmail.com

Lorena Mariel González Vitavar: lorena.gonzalez@uap.edu.ar

Heitor Barbosa Alves: heitor_98@hotmail.com

 

Abstract

Introduction: The skeletal muscle is the largest endocrine organ of human body and have this role through peptides and proteins known as myokines. The myokines are cytokines that are produced and secreted by the skeletal muscle in response to the stimulus of contraction, acting locally and/or be released in the circulation and influence other distant tissues. Physical exercise is a potent stimulus for molecular adaptations in the organism, and when practiced with regularity, promotes structural and functional adaptations in skeletal muscle. Therefore, physical exercise has a direct action on the concentrations of myokines. Objective: Based on this, this research investigated, through a systematic literature review, the responses of myokines concentrations from the stimulus of physical exercise. Methods: Searches were carried out by two researchers independently, in the Scielo, Pubmed and Virtual Healthy Library databases, analyzing articles published between 2009 and 2020, after a careful selection process in four stages, the works that reached the third stage were read in full and submitted to quality analysis using a critical review form. Results: At the end of the process, 12 articles were selected to compose the discussion. Conclusion: The analyzed articles show that physical performance, both acute and chronic, is capable of significantly modulating the concentration of several myokines, promoting an increase in many such as IL-6, IL-15, BDNF and apelin, in addition to a significant decrease in muscle myostatin.

Keywords: exercise; skeletal muscle fibers; cytokines.

 

Resumo

Introdução: O músculo esquelético é o maior órgão endócrino do corpo humano e possui esse papel a partir de peptídeos e proteínas conhecidos como miocinas. As miocinas são citocinas produzidas e secretadas pelo músculo em resposta ao estímulo das contrações, podendo agir localmente e/ou cair na circulação e influenciar outros tecidos distantes. O exercício físico é um potente estímulo para adaptações moleculares no organismo e, quando regularmente executado, induz adaptações estruturais e funcionais no músculo esquelético. Sendo assim, o exercício físico possui ação direta nas concentrações dessas miocinas. Objetivo: Baseado nisso, esta pesquisa teve como objetivo investigar, através de uma revisão sistemática de literatura, as respostas das concentrações de miocinas a partir do estímulo do exercício físico. Métodos: As buscas foram realizadas por dois pesquisadores de forma independente, nos bancos de dados do Scielo, Pubmed e BVS, analisando artigos publicados entre 2009 e 2020. Após processo de seleção criterioso em quatro etapas, os trabalhos que chegaram até a terceira etapa foram lidos na integra e submetidos a uma análise de qualidade por via formulário de revisão crítica. Resultados: Ao final do processo, foram selecionados 12 artigos para compor a discussão. Conclusão: Os artigos revisados demonstram que o exercício físico, tanto de forma aguda quanto de forma crônica, é capaz de modular de forma significativa a concentração de diversas miocinas promovendo o aumento da concentração das mesmas, por exemplo da IL-6, IL-15, BDNF e apelina, além de diminuição significativa de miostatina muscular.

Palavras-chave: exercício físico; fibras musculares esqueléticas; citocinas.

 

Introduction

 

Skeletal muscle (SM) has a great adaptative potential, being the intracellular signaling promoted by muscle contraction a strong mechanism to molecular and functional adaptation to muscle itself. Through stimulus caused by regular exercise training is possible to increase protein synthesis into SM, promoting higher functional capacity and performance [1].

Exercise is largely recommended both in prevention and as treatment to metabolic diseases by its anti-inflammatory (AI) role and as a metabolism regulator. In this scenario, the SM has an important role due the production and release of many cytokines and another peptide, called myokines by Pedderson et al. [2] in 2003.

These myokines can, in several cases, have AI role not only inside the muscle, but may be released into bloodstream and be transported to another organs and tissues. It can stimulate immunological responses and contrast with the deleterious effects of some cytokines produced by adipose tissue (AT), for example the tumor necrosis factor (TNF) [3,4]

Beyond that, the scientific literature shows evidences indicating that exercise training has the potential to directly alter the circulating levels of myokines, increasing production and release of many myokines, as interleukins (IL), IL-15 and IL-6 [4,5].

Although the importance of myokines be notable, considering that it allow communication between SM and other tissues, is still unclear how is their responsiveness to different exercise stimulus, as type, intensity and volume of exercise training. The knowledge of these responses can help to build a better exercise prescription aiming specific benefits promoted by higher myokines concentrations.

Besides that, there are some studies analyzing the effects of exercise into myokines concentrations, leading us to consider this review relevant, summarizing systematically the actual evidences in this field. Based in the knowledge of myokines responses, the professional of exercise prescription can be more specific to prescribe the exercise aiming to modulate properly one or more myokines. Based in these rational, the aim of this systematic review was to verify the responses of myokines concentration from exercise stimulus.

 

Methods

 

Determination of databases, research strategy and combinations

 

A systematic review was carried out based on bibliographic research of studies that analyzed the biological responses of myokines from the exercise stimulus. The research of the articles was performed by two independents researchers in December 2019, in the following electronic databases: Pubmed, Scielo and Virtual Health Library (in portuguese Biblioteca Virtual em Saúde [BVS]).

The selection of the descriptors used was made based on health science descriptors. In the searches for the articles the terms “myokines” and “effects of exercise” were used in the following combinations in English and Portuguese languages “skeletal muscle’’ AND “myokines”, “effects of exercise” AND “production of myokines”.

Was performed the PICO strategy: P – Participants in studies with exercise who dosed myokines; I - Interventions with systematic exercise of any type; C – Comparisons of results with theirselfs pre and posts results; O – Outcomes of exercise concentrations of circulating myokines.

To better organization of references, we organized than in an Excel spreadsheet 2013.

 

Search plan steps

 

Search plan was divided in four steps (stages). In the first step was identified 197 publications potentially eligible to review. Then, in second step, the “2009 to current” and “human” filters were used to find studies closer to the proposed theme, resulting in 45 studies.

In third stage, the titles, abstracts and conclusions were read in order to verify their suitability for the purpose to this review. In addition, was applied the inclusion criteria established for the paper’s selection. Were included the papers that: a) original cross-sectional or longitudinal work; b) with at least one physical exercise session; c) reporting the effects of exercise on myokines concentrations. After analyzing the studies, 18 publications were selected and analyze in the next step.

In the fourth stage of article selection, the established exclusion criteria were performed. To begin, the papers were fully read by two independent researchers and were excluded papers that: were duplicated; b) those that did not reached 10 points or more in the critical review of Law et al. [6], and c) myokines that were not be analyzed at least in two different papers.

 

Results

 

At the end of the fourth stage, 12 papers were selected to compound this review. It Is important to note that in all steps of search the papers and analyzes were conducted by two independents researchers using the statistical software SPSS 22.0 and the Kappa concordance test [7] to check the level of agreement between the researchers. As a result, values were always above 0.80 and P < 0.001, indicating almost perfect concordance between researchers. In this analysis, values up to 0.19 indicate poor agreement, between 0.20-0.39 mild agreement, 0.40-0.59 moderate agreement, 0.60-0.79 substantive agreement and between 0.80-1.00 indicates almost perfect agreement [7]. For a better understanding of the results, Figure 1 shows the number of studies during all the pre-established stages.

 

 

Figure 1 - Flowchart of the steps of the systematic review

 

Table I shows the score obtained by the studies selected using the instrument proposed by Law et al. [6]. It aims to classify the quality of studies and has 15 items.

However, item 4 does not score, as it is only to distinguish the type of study, so item 4 was removed from our analysis and item 5 became 4 and so on, totaling 14 items that were scored below in the table. A quality cut-off point of 10 points was defined, that is, the article that did not score at least 10 items would be eliminated from the review. The items that were scored were marked with an “x” while those that were not scored were left blank.

 

Table I - Score of studies in the critical review form by Law et al. (1998).

 

 

The profile of the 12 selected studies that met the inclusion and exclusion criteria was described in Chart 1. The total number of participants was 224 individuals, 74.2% (166) of whom were male and only 13.8% (31) women. Two studies did not report the gender of the sample. The age range of study participants ranged between 18 and 65 years.

Regarding study designs, 75% (9) were cross-sectional, while only 25% (3) evaluated biological responses in a longitudinal way. The response of myokines by stimulating resistance exercises (RE) was evaluated in 50% (6) studies. In turn, 50% (6) studies analyzed aerobic exercises (AE). Finally, the Elisa Kit was the most used enzymatic method of analysis in research.

 

Chart 1 - Profile of the selected studies. (see PDF)

 

Chart 2 shows the myokines response concentrations from the exercise stimulus. It is observed that IL-6, IL-15 and myostatin were the target of 4 studies each one, standing out, as the myokines of greatest interest in literature when it comes to response through exercise.

 

Chart 2 - Myokines responses after exercise. (see PDF)

 

Discussion

 

The aim of the present study was to systematically review the response of myokines after exercise training. To better understanding the data, we will initially address the actions of the myokines that will be discussed, to later describe the effects of exercise on them.

 

Myokines actions

 

IL-6, the first myokine described, was showed by Steensberg et al. [8] in 2000. In addition to being produced by SM as a result of muscle contraction, is also produced in other tissues, as liver, for example. There is evidence that IL-6 acts stimulating the proliferation of satellite cells after acute damage in the SM, and, therefore, having a role in muscle hypertrophy [9].

When in physical exercise, the release of IL-6 occurs independently of release of TNF-α [10], possessing, thus, AI capacity. In this conditions, IL-6 acts inhibiting the production and secretion of TNF-α and its soluble receivers, as well, blocking IL-1 and IL-10 receivers [11]. Chronically, the levels of IL-6 are lowed after an exercise program, however, is also reported a better AI state in individuals that practiced exercise [12]. A possible explanation to this paradox, may be the fact that exercise modulates the release of IL-6 in other tissues, as in the immune system, consequently, lowering the release of IL-6 associated to TNF-α. The scientific literature shows that higher circulating levels of IL-6 are associated with physical inactivity and higher risk of metabolic syndrome [3,11,13].

Another myokine that has been studied in recent years is the IL-15. This myokine, similar with many other molecules produced in the body, promotes several effects in different organs. These effects include signaling to muscle hypertrophy, in additional to acting on lipidic metabolism [14], reducing the deposition of lipids and reducing the mass of white adipocytes cells. In the immune system, IL-15 acts mobilizing natural killer (NK) cells, that in its turn, act reducing tumor growth [15]. In bone tissue, associated with fibroblast growth factor (FGF) 21, IL-6 helps with bone mineralization, consequently aiding bone formation and repair after fracture [3,16].       

We know that not all substances produced by muscular secretome assists in synthesis of other tissues, and myostatin is a good example of a myokine that acts limiting the muscle hypertrophy. Myostatin belongs to the family of transforming growth factor and with higher plasma levels of this myokine being observed in obese and sedentary individuals [17,18]. In addition to this limiting effect on muscle growth, myostatin has an important role in bone tissue and adipose tissue. In bone tissue, myostatin has acts opposite to IL-15, making mineralization and post-fracture repair difficult. In adipose tissue, therefore, evidence shows that myostatin triggers the signaling to hypertrophy of adipose tissue cells [16].

When performed acutely and chronically, the exercise downregulates myostatin levels in the tissues previously mentioned [19]. Evidence points to a large reduction of myostatin levels after one single session of exercise (56%), and in a longitudinal way, exercise training can reduce 34% of myostatin levels. In addition, a reduction of 48% was observed in elderly after an exercise program of training [20].

Another important myokine modulated by exercise is the brain-derived neurotrophic factor (BDNF), which in central nervous system, acts to maintain or improve cognitive activity by regulating neuronal survival, facilitating synaptic plasticity, neurogenesis and improving the memory process. BDNF also has a role in neuroprotection against anxiety and depression [16,21].

Finally, apelin is a myokine that has receptors in various organs, as the kidneys, lungs, adrenal gland, heart, pancreas and brain. It is important to increase the cardiac inotropism and is associated with insulin metabolism. Apelin also improves the mitochondrial capacity in SM and reduces muscle damage [22].

 

Myokines and exercise

 

Interleukin 6 (IL-6)

 

The study conducted by Oliver et al. [14] evaluated myokines acute late responses after traditional squat and in the cluster squat (with 30s intra-series interval and 150s interval between sets), both at 70% of a maximum repetition (1MR). This study demonstrated a significant increase in the IL-6 concentration after exercise, but there were no significant differences between the kinds of squat. These findings can be partially explained by the fact that IL-6 can both acts as an anti-inflammatory factor and as an energy sensor in the cell [24]. Once having a bigger energy demand and increased gluconeogenesis, IL-6 is released, and both, the intensity and volume of exercise, affect its releasing.

In a study conducted by Wahl et al. [25], when analyzed the responses of three different situations 1) cycling with an effort at 70% of peak power, over a period of 60 minutes, 2) cycling plus electrostimulation and 3) only electrostimulation. The authors observed that the concentration of IL-6 increased significantly during cycling both with, and without electrostimulation, but not in isolated electrostimulation. These findings corroborate with the idea that the production and release of IL-6 is related to the mechanotransduction stimulus trigged by muscle contraction.

In a study conducted by Zembron-Lacny et al. [26] related the late acute response of IL-6 in a normal running and running with eccentric emphasis. They found higher Il-6 concentrations after running with eccentric emphasis. These findings can be explained to complementary factors. First, in eccentric contractions there a bigger tendency to muscle damage. In second, IL-6 also acts in muscle repair, inducing the proliferation of satellite cells [9]. In this way, exercise with eccentric emphasis can increase the expression of IL-6 messenger ribonucleic acid (mRNA) in the muscle.

Bugera et al. [27] evaluated bilateral knee extension with and without blood flux restriction in low intensity and without blood flux restriction in high intensity in strength training experienced individuals. The researchers did not find serum detectible levels of IL-6. Since there is little time of exposure to exercise and that the fact that IL-6 together with AMP-activated protein kinase (AMPK) are the most powerful energy sensors in the cell. Increasing its expression when there is a high metabolic demand compatible with cyclic training of greater volume, in resistance training there is a greater activation of Phosphoinositide 3-kinases-Protein Kinase B- mammalian target of rapamycin (PI3K-AKT-mTOR) pathway, that, which, in addition to signaling for protein synthesis, inhibits AMPK pathway [28].

The studies described above corroborate with the literature about the fact that IL-6 acts as a metabolic sensor and its concentration increases while the glycogen concentrations drop both in the muscle as in the liver. In another hand, chronically, evidences point, to decrease in plasma concentration levels of IL-6 decrease after physical exercise [12].

 

IL-15

 

We found studies analyzing IL-15 myokine only acutely. In the study conducted by Perez-Lopez et al. [29] was found a significance increase in IL-15 levels after leg press and in bilateral knee extension. IL-15 was more than 5 folds higher after exercise. This finding can be explained due to the mediating role of IL-15 in the elevation of myofibrillar protein synthesis observed in SM after a single session of a resistance training. This finding corroborates the study by Oliver et al. [23] who also found a significant post-EF increase for lower limbs.

On the other hand, Bugera et al. [27] when evaluating the resistance training with and without blood flow restriction, found no significant difference in IL-15 concentrations after exercise. Contrary to the two researches previously mentioned, Bugera et al. [27] adopted a submaximal exercise protocol and the total exercise volume was also lower. In our opinion, these results point to the need for high volume application to stimulate the response of this myokine. In addition, fatigue appears to play an important role in IL-15 secretion, as in the studies by Oliver et al. [23] and Perez-Lopez et al. [29], since this myokine plays a role in the response to muscle fatigue.

Tamura et al. [30] evaluated the acute response of IL-15, 30 minutes after an exercise performed on the treadmill at 70% of maximum heart rate, finding a significance increase in IL-15 levels after 10 minutes of recovery. The aforementioned studies indicate that regardless of the type of exercise, whether aerobic or resistance training, the contractile activity of the SM can trigger the production and release of IL-15, which may influence the mediation of systemic and local benefits from the exercise. From these studies, it seems to us that volume is a more important variable in resistance training than in aerobic training for the release of IL-15.

 

Miostatin

 

In an interesting study conducted by Carvalho et al. [18] the myostatin response was acutely evaluated after a maximal treadmill test and isokinetic exercise for lower limbs in three distinct groups composed of eutrophic individuals (EI), metabolically healthy obese individuals (MHOI) and obese individuals metabolically unhealthy (OMUH). Being classified as OMUH individuals who had insulin resistance and at least three of the five criteria for Metabolic Syndrome according to Panel III of adult treatment of the National Cholesterol Education Program [31].

The results showed that myostatin was elevated only in OMUH, because unhealthy obesity was associated with events such as insulin resistance, metabolic syndrome, TNF-α and low muscle mass. In addition, and perhaps more importantly, the authors also determined in this study the ideal cutoff point for myostatin concentration, which is> 505.1 pg / ml. These findings may prove to be useful in future studies and also in the monitoring of cardiometabolic disorders.

Myostatin response was evaluated in a longitudinally way by Hitel et al. [32] in a program of moderate exercise, where after each exercise session was measured myostatin levels. The authors analyzed myostatin levels after a 9 months exercise program in sedentary hyperinsulinemic individuals, using two different methods: western blotting and ELISA. In the western blotting method was found 37% reduction in myostatin levels, however, through the ELISA method, a 21% reduction in these levels was found. In our view, this discrepancy in values should be observed with caution, because most of the studies reviewed here adopted the ELISA method as a way of quantifying myokine concentrations.

Hjorth et al. [33] evaluated the myostatin concentrations during 12 weeks of exercise, both resistance and aerobic training in healthy individuals and in individuals with dysglycemia. The authors found a significant drop of 7.5% in the group with dysglycemia that was in the exercise training. However, acutely, the myostatin levels was found increased, in addition, a moderate positive correlation was found with glycolytic fiber, indicating that the greater the glucose consumption, more myostatin is produced and released. This find is corroborated by the moderated negative correlation for myostatin concentration and slow contraction oxidative fibers.

Kerschan-Schindl et al. [34] evaluated myostatin levels after 246 km marathon, the authors found a 12% increase in myostatin levels in the post-race compared to the pre-race. Despite this study finding higher levels of myostatin after exercise, possibly due to the level of effort required in an ultramarathon, the trend shown in the studies cited above is that myostatin appears reduced after physical training performed chronically. Still, the scientific literature is not clear when explaining the reason for this reduction, but it is known that there is a crosstalk between the skeletal muscle and the liver, where, in this case, the release of follistatin is increased by the liver and this substance acts by inhibiting the production and release of myostatin by the SM, which could chronically lead to these findings [3].

 

Brain Derived Neurotrofic Factor (BDNF)

 

In the study by Fortunato et al. [35], there was an increase in BDNF expression only for the group trained in resistance training, compared to the control group. In the study by Wahl et al. [25], the authors found greater increases in BDNF concentration after 60 minutes on the isolated cycle ergometer, followed by the cycle ergometer plus electrostimulation condition. These findings contribute to the notion that muscle contraction is a potent stimulator of BDNF release. Recently, the functioning of two pathways of crosstalk between muscle-brain has been discussed.

In the first pathway, moderate to high intensity exercise stimulates the secretion of cathepsin B, which manages to cross the blood-brain barrier (BBB) and stimulate the production of BDNF messenger ribonucleic acid (mRNA) [36]. In the second pathway, exercise stimulates the release of irisin into the bloodstream and irisin, in turn, would be able to cross the BBB and stimulate the production of BDNF in the hippocampus region [37].

 

Apelin

 

In the study by Fortunato et al. [35] it was shown that resistance training was able to increase plasma levels of apelin in the group with people not trained in resistance exercises, 2 hours and 24 hours after the end of session. In the study by Sanchis-Gomar et al. [38] apelin was evaluated longitudinally during a professional football season, with a significant increase in its concentration in the first three months of the season. However, although this myokine is related to the improvement of mitochondrial capacity [39], this increase was not correlated with the players' sports performance. Based on that, the authors consider that this myokine should not be considered as a performance biomarker. In our opinion, more studies need to be carried out with this theme, not only in football, but in other sports.

Considering the acute results of the studies above. We consider important to highlight the hypotensive effect of apelin already demonstrated in the literature and how its secretion can benefit hypertensive individuals. This is due to phosphorylation of the enzyme nitric oxide synthase endothelial, consequently causing an increase in the production of nitric oxide [40]. In hypertensive subjects, the levels of apelin are decreased, mainly due to hemodynamic changes caused by the pathology [41]. Longitudinally, the study by Izadi et al. [42] demonstrated that high-intensity interval training can increase the secretion of apelin and nitric oxide in hypertensive individuals.

 

 

Figure 2 - Summary of myokine responses and actions.

 

Limitations and future directions

 

We highlight as limitations, the fact that of the selected articles, a small number of studies (only three), evaluated the responses of myokines to exercise in a chronic way and that different intervention methodologies resulted in difficulty in comparing the findings. As future directions, we suggest that a pattern in the intervention methodology, with respect to volume and intensity, be replicated in different studies, with the aim of verifying whether there is a difference between the results, and that studies investigating the effect of different environmental temperatures are produced and exercise conditions in the responses of myokines to increase the external validity and application of the exercise prescription considering the concentrations of myokines.

 

Conclusion

 

Based on the findings of this review, the ability of both aerobic training and resistance training to stimulate changes in the concentrations of different myokines is evidenced. It is also observed that the volume and intensity of exercise play a regulatory role in the production and secretion of myokines.

In addition, it was possible to observe that, both acutely and chronically, the practice of exercise provided significant changes in the release of myokines and that not all respond in the same way, such as IL-6 and BDNF, which increases after the exercise session, however, on the other hand, myostatin tends to decrease.

It was also possible to verify that most studies analyzed IL-6, IL-15 and myostatin, which suggests a specific interest in the literature to investigate the concentrations of these myokines. On the other hand, this creates a gap in the study of other myokines that should be further investigated, such as apelin and BDNF.


Potential conflict of interest
The authors declare that there is no conflict of interest


Financing source
Pernambuco State Science and Technology Support Foundation (FACEPE)


Authors' contributions
Conception and design of the research, critical review of the manuscript: Leandro Paim da Cruz Carvalho; Data collection: Heitor Barbosa Alves, Matheus Borges da Cruz Gomes, Ícaro Cerqueira da Silva Oliveira; Writing ofthe manuscript: Heitor Barbosa Alves, Matheus Borges da Cruz Gomes, Leandro Paim da Cruz Carvalho, Ícaro Cerqueira da Silva Oliveira, Pedro Henrique Silva Santos, Ariel Custódio de Oliveira II, Lorena Mariel González Vitavar

 

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