Immunology Letters 203 (2018) 1–5

Contents lists available at ScienceDirect

Immunology Letters
journal homepage: www.elsevier.com/locate/immlet

Myokines, physical activity, insulin resistance and autoimmune diseases T

a a,b c
Buenaventura Brito Díaz , Delia Almeida González , Fadoua Gannar ,
⁎
M. Cristo Rodríguez Péreza, Antonio Cabrera de Leóna,d,
a
Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
b
Immunology Section, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
c
Laboratory of Biochemistry-Human Nutrition, Faculty of Sciences of Bizerte, Carthage University, Tunis, Tunisia
d
Facultad de Medicina, Universidad de La Laguna, La Laguna, Spain

A R T I C LE I N FO A B S T R A C T

Keywords: Myokines are peptides produced and released by myocytes of muscle fibers that influence physiology of muscle
Myokines and other organs and tissues. They are involved in mediating the beneficial effects that exercise has on health.
Insulin resistance More than one hundred have been identified and among them are IL6, myostatin, irisin, mionectin and decorin.
Autoinmune diseases Physical inactivity leads to an altered response of the secretion of myokines and resistance to them; this leads
to a pro-inflammatory state that favors sarcopenia and fat accumulation, promoting the development of cardi-
ovascular diseases, insulin resistance, and diabetes mellitus type 2.
Some myokines, including irisin, are responsible for the improvement that exercise produces in many chronic
diseases such as type 2 diabetes and cardiovascular diseases, some types of cancer and many autoimmune
diseases such as idiopathic inflammatory myopathy, rheumatoid arthritis, systemic lupus erythematosus and
inflammatory bowel disease.

1. Introduction significantly to protein metabolism, body glucose and the production of

glutamine, and participates in the supply of nutrients to the immune
Muscles are characterized by their mechanical activity as well as system and other tissues [2].
their role in energy metabolism. Skeletal muscle, in non-obese in- Skeletal muscle contains resident populations of immune cells and
dividuals, is the largest organ in the body and has been identified as a its type and quantity are altered in endotoxemia, inflammatory myo-
secretor of “myokines”. pathies or in different types of muscle injuries. Within tissues, mono-
Myokines are peptides produced, expressed and released by myo- cytes differentiate into macrophages and acquire pro- or anti-in-
cytes of muscle fibers that influence the physiology of muscle and that flammatory phenotypes. This event requires a rigorous regulation in the
of other organs and tissues. These cytokines exert autocrine, paracrine interaction that takes place between muscle fibers and immune cells.
or endocrine effects both on the organs that surround them and on The muscle is the main organ for the discharge of glucose from the diet,
those located at a distance from them [1]. Myokines participate in the therefore the resistance to muscle insulin is essential for the develop-
regulation of energy homeostasis, in the metabolism of glucose and li- ment of insulin resistance throughout the body. Muscle inflammation
pids as well as in the stimulation of angiogenesis. These molecules have contributes to insulin resistance and in obesity, muscle cells show in-
been studied, mainly, in response to exercise or metabolic problems. flammatory responses [3]. Also, chronic inflammation is implicated in
the pathogenesis of insulin resistance and in atherosclerosis, neurode-
2. Immunology of skeletal muscle generation, and tumor growth [4].

Skeletal muscle maintains a defense system against inflammation by 3. Myokines

heat shock proteins and the production of myokines. Thus, it intervenes
in a bidirectional way in the systemic inflammatory signaling and in the More than one hundred have been identified and among them are
modulation of the inflammatory response. Also, it contributes IL4, IL6, IL7, IL-8, IL15, myostatin, leukemia inhibitory factor (LIF),

⁎
Corresponding author at: Unidad de Investigación, Hospital Universitario Ntra. Sra. de Candelaria, Carretera de El Rosario 145, 38010 Santa Cruz de Tenerife,
Canary Islands, Spain.
E-mail address: [email protected] (A.C. de León).

https://doi.org/10.1016/j.imlet.2018.09.002
Received 20 June 2018; Received in revised form 22 August 2018; Accepted 3 September 2018
Available online 05 September 2018
0165-2478/ © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
B.B. Díaz et al. Immunology Letters 203 (2018) 1–5

brain-derived neurotrophic factor (BDNF), insulin-like growth factor have a paracrine-endocrine effect depending from their dose [19]. On
(IGF1), fibroblast growth factor 2 (FGF2), fibroblast growth factor 21 the other hand, it is considered that muscle IL-6 has an important role
(FGF21), follistatin-related protein 1 (FSTL1), irisin, erythropoietin in anti-inflammatory activities and beneficial effects on health in rela-
(EPO), β-aminoisobutyric acid (BAIBA), CTRP15 (mionectin) and dec- tion to physical exercise. Nevertheless, the increase of IL-6 plasma le-
orin. vels represents a strong risk marker of chronic diseases associated with
low-level systemic inflammation and mortality [20,21].
4. Functions of the main myokines

IL-6 secreted from myocytes stimulates lipolysis in adipose tissue 6. Physical activity and myokines
while IL-6 from adipocytes induces insulin resistance in muscle [5]. In
addition to lipolysis, IL-6 exerts an increase in lipid oxidation in the Muscle contraction stimulates production and release of myokines
body [6]. Therefore, IL-6 administration to humans increases lipolysis, in the blood that can influence metabolism in various tissues and organs
fat oxidation and the elimination of glucose mediated by insulin [7]. In [22,23]. Skeletal muscle cells can produce and express cytokines be-
addition, this cytokine stimulates the production of cortisol [8]. IL-6 longing to different families. The most studied and first identified is
derived from brain and muscle provides an explanation of how to Glycoprotein 130 (gp130) that is a receptor, among others, from IL-6 and
regulate mood that influence muscle activity, performance and cogni- was discovered like a myokine because it increases up to 100 times in
tive function [9]. The regulation of the genes of IL-6 is related to the circulation during physical exercise [24]. Exercise causes an increase in
prototypical response of myokines to stress, and in the muscle it is or- cytokines that may have an anti-inflammatory, immunoregulatory and
ganized to respond to a wide variety of internal and external stressors. metabolic effect [25].
IL-6 may initiate protection processes, anti-inflammatory or repairers Skeletal muscle is able to express IL-6, IL-8 and IL-15, and exercise
throughout the body during conditions that threaten life. Also, it may plays a role in regulating the expression of these cytokines and their
be fundamental in the body’s response to acute stress [10]. possible functions in the metabolism [22]. It is known that, with phy-
IL-15 participates in the modulation of adipose tissue deposition sical activity, there is also an increase in decorin as well as a decrease in
[11]. Myostatin is involved in the skeletal muscle repair [1]. Mionectin myostatin [26]. Physical activity exerts favorable effects by reducing
acts as a postprandial signal derived from skeletal muscle to integrate chronic low-grade inflammation. These effects on the main in-
metabolic processes in other tissues; one of its functions is to promote flammatory mediators may be acute or chronic [21].
the absorption of fatty acids by cells [12,13]. BDNF is involved in fat During muscle contractions IL-1 receptor antagonists and soluble
oxidation mediated by AMPK and other myokines such as IGF1, FGF-2 TNF receptor are released, that contribute to anti-inflammatory actions
and FSTL-1, are osteogenic factors that improve the endothelial func- [27]. During the first hours after an intense resistance exercise, nuclear
tion of the vascular system [14]. Irisin is a more recently identified factor- kB (NF-kB) is activated in human skeletal muscle, and is im-
myokine [15], that transform white fat into brown fat [16]. plicated in the transcriptional control of myokines. This factor is known
to be fundamental for the post-exercise inflammatory response [28]. It
5. Relationship between muscle and adipose tissue is suggested that myokines released during exercise can exert their anti-
inflammatory effect through a specific effect on the reduction of visc-
The interaction between these two organs occurs through cell sig- eral fat and/or directly by the induction of an anti-inflammatory am-
naling pathways and by secretion of proteins by adipose tissue (adi- bient. Moreover, other myokines work locally in the muscle exerting
pokines) and muscle (myokines) [17]. Both, adipokines and myokines, their effects on signaling pathways involved in fat oxidation and glu-
include proteins involved in inflammation IL-6, IL-8 and MCP-1. With cose uptake.
muscle contraction, myokines are released with endocrine action and Physical exercise induces a chain of alterations in the transcriptome
may mediate direct anti-inflammatory effects on visceral fat. and proteome of the skeletal muscle whose result produces modifica-
Other myokines act locally in the muscle and exert their effects on tions of the physiology of the muscle [29]. Muscle development is in-
signaling pathways involved in fat oxidation and glucose uptake [4]. duced with the increase of fiber, systemic hormonal production and the
The complex paracrine/endocrine interconnection between adipokines alteration of local myokines such as myostatin, leukemia inhibitory
and myokines reflects important implications in processes such as the factor (LIF), IL-6 and IL-7 [14,30]. The activation of a proteinkinase
control of lipolysis, insulin sensitivity and obesity prevention. In addi- (Akt) related to cell signaling has been implicated in the control of
tion, they may be important in the development of therapeutic strate- muscle hypertrophy. The identification of myokines conferring the
gies against cancer cachexia since its pathophysiology is based on the phenotypic changes caused by the induction of myogenic Akt has been
interaction between muscle and adipose tissue, mediated by free fatty suggested. The follistatin-like 1 (FSTL1) is able to promote re-
acids, various adipokines and myokines [18]. vascularization in ischemic limbs and protect the heart from ischemic
The myokines IL-6, IL-15, irisin, BDNF, ANGPTL4, FGF21, myo- stress [31]. Myokines are involved in the metabolic process of angio-
nectin and MCP-1 are also known to be secreted by adipocytes. Thus, genesis and muscle formation. The production of myokines is depen-
arises the question why proinflammatory adipokines are increased in dent on the type of muscle contraction produced during exercise [32].
pathological processes, like the obese state and, however, behave Furthermore, muscles release reactive oxygen species (ROS) and
beneficially after exercise.The answer seems to be that, both, adipo- reactive nitrogen species (RNS) that are detectable at low levels during
kines and myokines, have autocrine effects within their corresponding rest and higher levels during muscle contractions. The importance of
tissues.In addition of being involved in an endocrine interaction with ROS and the chemistry of thiol in fatigue is observed [33] as well as, the
other tissues. Therefore, depending on the amount of cytokines/myo- redox regulation in relation to glucose transport and the regulation of
kines secreted in the serum, these molecules seem to have a beneficial carbohydrate metabolism in skeletal muscle [34]. Exercise transiently
effect (if the concentration is low) or an adverse effect (if your con- induces in skeletal muscle the production of ROS capable of stimulating
centration is high) on the target tissue. However, its lack is also dele- the production of cytokines and participating in the regulation of cell
terious. signaling. ROS and myokines have been suggested as important factors
So, if the concentration of the same cytokine (for example IL-6, in muscle adaptation to exercise [29].
derived from both muscle and adipose tissue) increases in serum, the A long time of inactivity produces “resistance to the myokines” that
systemic effect will be proinflammatory adverse. While if its con- is associated with chronic subclinical inflammation [2,22,25,32,35]
centration decreases (IL-6, derived from muscle tissue), then it will
have a beneficial proinflammatory effect, that means these substances

2
B.B. Díaz et al. Immunology Letters 203 (2018) 1–5

6.1. Physical activity and IL-6 the vicious circle of sarcopenia and the accumulation of fat (especially
visceral), promoting the development of cardiovascular diseases, dia-
IL-6 is a pleiotropic cytokine produced practically by all nucleated betes mellitus type 2, cancer, dementia and depression [47]. In addition
cells including myocytes released in response to muscle contraction to promoting the development of neurodegeneration, as well as insulin
[36]. In resting muscle, the IL-6 gene is silent. Exercise activates tran- resistance, atherosclerosis and tumor growth. In consequence, seden-
scription factors that regulate the synthesis of IL-6 [7] producing a local tary lifestyle is an independent risk factor for the accumulation of
and systemic increase in IL-6 levels [37]. This increase is accompanied visceral fat and the activation of a network of systemic inflammatory
by an increase in the proinflammatory cytokines IL-1ra (Interleukin 1 pathways [48].
receptor antagonist) and IL-10 [38]. Carbohydrate supplementation The fragility associated with age and the reduction of physical ac-
during exercise inhibits the release of IL-6 [8]. After muscle contrac- tivity contribute to a progressive loss of muscle mass and function
tion, IL-6 is released into the circulation in amounts dependent on the (sarcopenia). Resistance, strength and stretching exercises have a sig-
intensity and duration of exercise [39]. The energy status of the muscle nificantly greater effect than those produced by drugs [49]. Further-
is determined by the glycogen content before exercise. Glycogen more, skeletal muscle aging is a risk factor for the development of
modulates the production of IL-6 behaving as an "energy sensor". A low various age-related diseases such as metabolic syndrome, cancer, Alz-
muscle glycogen level, before exercise, increases the expression and heimer's disease and Parkinson's disease [50].
release of IL-6 [40]. The main source of acute increase in plasma IL-6 Evidence of the effectiveness of exercise interventions for chronic
levels during exercise are myofibrils [41]. Exercise induces, in the long conditions has been described and discussed: hip and knee osteoar-
term, an increase in muscle glycogen content in pre-exercise. This may thritis, non-specific chronic low back pain, prevention of falls, heart
explain the decreased expression and secretion of IL-6 after a regular failure, coronary disease, chronic obstructive pulmonary disease,
period of resistance exercise. Regular training decreases the basal chronic fatigue syndrome and type 2 diabetes [51].
plasma level of IL-6 and increases the basal expression of the mRNA of
IL-6 receptor in skeletal muscle, resulting in greater sensitivity to IL-6. 7.1. Insulin resistance and type 2 diabetes
In addition, it has been suggested that the muscle contraction that
induces the expression of IL-6 is independent of the NFkB pathway Sedentary lifestyle increases low-grade systemic inflammation
[24]. It seems to be mediated by the activation of c-Jun N-terminal through chronic increase in IL-6 levels, TNF-α and IL-1β, and thus,
kinase (JNK) and activator protein-1 (AP1) [42]. Endogenous glucose increasing the risk of insulin resistance and type 2 diabetes.
production is stimulated by IL-6 during exercise [43]. However, this Conversely, regular physical activity reduces systemic inflammation
effect seems to be related to another factor not yet identified but re- with decreased secretion of proinflammatory myokines and an acute
leased during the contraction, since infusion of IL-6 alone can not in- increase in IL-6, IL-10, IL-1ra, sTNFR, CHI3L1 and CX3CL1, so reducing
crease hepatic glucose production in resting individuals [38]. the risk of insulin resistance and type 2 diabetes. Furthermore, with
The identification of the production of IL-6 during physical activity exercise there is a decrease in visceral fat, and in the expression of TLRs
generated a great interest on its metabolic role creating a paradox. In and an increase of cortisol and adrenaline that, at the same time, de-
summary, IL-6 is produced remarkably and is released in the post-ex- crease the production of proinflammatory cytokines.
ercise period when the action of insulin increases, but on the other Myokines are important mediators of the health effects of regular
hand, it has been associated with obesity and the reduction of insulin physical activity. These cytokines have been implicated in the regula-
action. This brings attention to IL-6 in both health and disease, in its tion of glucose / fatty acid metabolism and in insulin secretion as well
regulation, its signaling pathways in skeletal muscle and its role in as in insulin sensitivity. Physical inactivity could be one of the main
metabolism [24]. causes of the development of metabolic disorders [16].
It is not only IL-6. Also, IL-8 could play a beneficial role in cell Myokines, by means of the anti-inflammatory effects on the muscle
adaptation in response to exercise [26], and Irisin is a mediator of the itself, can counteract insulin resistance induced by TNF [4]. Adipose
beneficial effects of physical activity [15]. tissue contributes to the production of TNF-α, which is reflected by high
levels of sTNFR, IL-6, IL-1 receptor antagonist and the C-reactive pro-
7. Myokines and disease tein. It has been suggested that TNF-α, instead of IL-6, leads to insulin
resistance and dyslipidemia, and that IL-6 is a marker of metabolic
Low-grade chronic inflammation is a key factor in the pathogenesis syndrome rather than a cause [52]. Thus, IL-6 stimulates the appear-
of chronic non-communicable diseases that are reaching epidemic ance in circulation of other anti-inflammatory cytokines such as IL-1ra
proportions throughout the world. Among them cardiovascular dis- and IL-10 and inhibits the production of the proinflammatory cytokine
eases, type 2 diabetes, some types of cancer (colon, breast) and de- TNF-α. In addition, IL-6 improves the "turn-over" of lipids, stimulating
mentia. lipolysis, as well as fat oxidation. This suggests that regular exercise
Myokines may be involved in mediating the beneficial effects that induces suppression of TNF-α and offers protection against insulin re-
exercise has on health. It has been suggested that some of the effects of sistance induced by TNF-α. Given the increase in IL-6 in obese patients,
exercise are based on its anti-inflammatory actions [44]. Myokines this cytokine has been implicated as a co-inducer of the development of
produce humoral and metabolic changes that can contribute to the insulin resistance and type 2 diabetes associated with obesity [53].
protection induced by exercise against several chronic diseases [45]. Nevertheless, IL-6 can participate in protection against type 2 diabetes
These inflammatory disorders are associated with a sedentary lifestyle [36] propitiating an anti-inflammatory environment by inhibiting the
along with the abundant intake of calories [20]. Some myokines are proinflammatory effect of the cytokine TNF-α [7].
involved in the protection against type 2 diabetes and cardiovascular IL-1β is involved in the damage of the β-cells of the pancreas
diseases [46]. On the other hand, inflammatory cytokines play an im- whereas TNF-α seems to be a key molecule in peripheral resistance to
portant role in the loss of muscle mass that occurs in certain systemic insulin. Human studies suggest that the acute / moderate elevation of
diseases. IL-6, triggered by exercise, exerts direct anti-inflammatory effects de-
Since many proteins produced by skeletal muscle depend on the rived from the inhibition of TNF-α and the stimulation of IL-1ra, which
contraction, physical inactivity probably leads to an altered response of limits IL-1β signalization. In addition, IL-6 has a direct impact on glu-
myocyte secretion. Consequently, a state that could lead to a potential cose and lipid metabolism. It should be noted that physical activity
mechanism for the association between sedentary behavior and many represents a natural anti-inflammatory action and a strategy to improve
chronic diseases [14]. Physical inactivity promotes an imbalance be- the metabolism [54]. Myotubes of patients with type 2 diabetes are
tween myokines that leads to a pro-inflammatory state. It also favors resistant to the acute effects of IL-6 on glucose metabolism [55].

3
B.B. Díaz et al. Immunology Letters 203 (2018) 1–5

To understand the mechanisms linked to the anti-inflammatory ef- ANGPTL4: Angiopoietin-like 4.

fects of exercise, one must take into account the endocrine effects of FGF-21: fibroblast growth factor 21.
myokines on immune cells [16]. In this sense, the endocrine effects of FGF-2: fibroblast growth factor 2.
adiponectin on skeletal muscle are due to the antidiabetic effects of this LIF: Leukemia inhibitory factor.
adipokine. Overexpression of adiponectin confirmed the functional IGF1: Insulin-like growth factor.
importance of adiponectin production in muscle cells, through an in- FSTL1: Follistatin-related protein 1.
crease in glucose uptake and insulin sensitivity. In addition, the in- EPO: Erythropoietin.
duction of obesity and insulin resistance, in rats with a diet high in fat BAIBA: β-aminoisobutyric acid.
and sucrose, leads to a decrease in the content of muscle adiponectin TNF-α: Tumor Necrosis Factor-α.
[56]. sTNFR: Soluble tumor necrosis factor receptors.
The exercise acts on genes involved in glycolysis, insulin signals, in IL-1ra: Interleukin 1 receptor antagonist.
GLUT and in the regulation of genes involved in biosynthesis and amino CHI3L1: Chitinase-3-like protein 1.
acid metabolism. This provides novel information on the potential CX3CL1: Chemokine ligand 1.
mechanisms to improve the metabolism alterations of glucose and PPAR PGC-1-alpha: Peroxisome proliferator-activated receptor and
amino acids associated with type 2 diabetes [57]. Insulin resistance in co-activator 1 α.
skeletal muscle leads to the production of myokines that negatively GLUT4: Glucose transporter type 4.
affect the function of β cells. Various myokines act on the proliferation CTRP15: Myonectin.
and survival of pancreatic β cells [58] facilitating a pathway to control
type 2 diabetes [59]. IL-6 is the protein, derived from muscle, that References
mediates communication between organs [60]. There is a correlation
between insulin resistance mediated by TNF-α and type 2 diabetes [61]. [1] K. Lizuka, T. Machida, M. Hirafuji, Skeletal muscle is an endocrine organ, J.
Pharmacol. Sci. 125 (2014) 125–131.
[2] A. Lightfoot, A. McArdle, R.D. Griffiths, Muscle in defense, Crit. Care Med. 37
7.2. Autoimmune diseases (2009) S384–S390.
[3] N.J. Pillon, P.J. Bilan, L.N. Fink, A. Klip, Cross-talk between skeletal muscle and
Myokines exert beneficial effects in patients with autoimmune dis- immune cells: muscle-derived mediators and metabolic implications, Am. J.
Physiol. Endocrinol. Metab. 304 (2013) E453–E465.
eases although their mechanism of action is not fully known. TNF-α is [4] C. Brandt, B.K. Pedersen, The role of exercise-induced myokines in muscle home-
involved in the loss of muscle mass characteristic of many autoimmune ostasis and the defense against chronic diseases, J. Biomed. Biotechnol. 2010
diseases. Idiopathic inflammatory myopathy is characterized by the (2010) 520258.
[5] P. Trayhurn, C.A. Drevon, J. Eckel, Secreted proteins from adipose tissue and ske-
presence of autoantibodies and the infiltration of inflammatory cells letal muscle-adipokines, myokines and adipose/muscle cross-talk, Arch. Physiol.
between and within the muscle fibers of skeletal muscle producing an Biochem. 117 (2011) 47–56.
irreversible process of atrophy of muscle fibers and their replacement [6] B.K. Pedersen, A. Steensberg, C. Fischer, C. Keller, P. Keller, P. Plomgaard,
M. Febbraio, B. Saltin, Searching for the exercise factor: is IL-6 a candidate? J.
by fat. It has been pointed out that the practice of exercise is beneficial,
Muscle Res. Cell. Motil. 24 (2003) 113–119.
in addition to this disease, for rheumatoid arthritis and for systemic [7] B.K. Pedersen, C.P. Fischer, Physiological roles of muscle-derived interleukin-6 in
lupus erythematosus [62,63]. Also, to help counteract some specific response to exercise, Curr. Opin. Clin. Nutr. Metab. Care 10 (2007) 265–271.
complications, it has been recommended to practice exercise in in- [8] B.K. Pedersen, A. Steensberg, C. Fischer, C. Keller, P. Keller, P. Plomgaard, E. Wolsk-
Petersen, M. Febbraio, The metabolic role of IL-6 produced during exercise: is IL-6
flammatory bowel disease [64]. an exercise factor? Proc. Nutr. Soc. 63 (2004) 263–267.
[9] B.K. Pedersen, M. Febbraio, Muscle-derived interleukin-6-a possible link between
8. Conclusions skeletal muscle, adipose tissue, liver, and brain, Brain Behav. Immun. 19 (2005)
371–376.
[10] S.S. Welc, T.L. Clanton, The regulation of interleukin-6 implicates skeletal muscle as
The production and release of myokines into the blood is estimu- an integrative stress sensor and endocrine organ, Exp. Physiol. 98 (2013) 359–371.
lated by the muscle contraction. These cytokines produce humoral and [11] L.S. Quinn, B.G. Anderson, L. Strait-Bodey, A.M. Stroud, J.M. Argilés, Oversecretion
of interleukin-15 from skeletal muscle reduces adiposity, Am. J. Physiol.
metabolic changes that contribute to the protection induced by exercise Endocrinol. Metab. 296 (2009) E191–E202.
againts insulin resistance, type 2 diabetes, cardiovascular and auto- [12] M.M. Seldin, G.W. Wong, Regulation of tissue cross-talk by skeletal muscle-derived
immune diseases. myonectin and other myokines, Adipocyte 1 (2012) 200–202.
[13] M.M. Seldin, J.M. Peterson, M.S. Byerly, Z. Wei, G.W. Wong, Myonectin (CTRP15),
The relationship between muscle and adipose tissue occurs through
a novel myokine that links skeletal muscle to systemic lipid homeostasis, J. Biol.
the secretion of myokines and adipokines. Depending on the amount of Chem. 287 (2012) 11968–11980.
secreted cytokines in the serum, these molecules seem to have a ben- [14] B.K. Pedersen, M.A. Febbraio, Muscles, exercise and obesity: skeletal muscle as a
secretory organ, Nat. Rev. Endocrinol. 8 (2012) 457–465.
eficial or an adverse effect.
[15] P. Boström, J. Wu, M.P. Jedrychowski, A. Korde, L. Ye, J.C. Lo, K.A. Rasbach,
Myokines released during exercise can exert their antiinflammatory E.A. Boström, J.H. Choi, J.Z. Long, S. Kajimura, M.C. Zingaretti, B.F. Vind, H. Tu,
effect through a specific effect on the reduction of visceral fat or di- S. Cinti, K. Højlund, S.P. Gygi, B.M. Spiegelman, A PGC1-α-dependent myokine that
rectly by the induction of an antiinflammatory ambient. drives brown-fat-like development of white fat and thermogenesis, Nature 481
(2012) 463–468.
Myokines by mean of their antiinflammatory effects on the muscle [16] K. Eckardt, S.W. Görgens, S. Rashke, J. Eckel, Myokines in insulin resistance and
itself can counteract the induction of insulin resistance and the loss of type 2 diabetes, Diabetologia 57 (2014) 1087–1099.
muscle mass characteristic of many autoimmune diseases. [17] M. Bonnet, I. Cassar-Malek, Y. Chilliard, B. Picard, Ontogenesis of muscle and
adipose tissues and their interactions in ruminants and other species, Animal 4
(2010) 1093–1109.
Disclosure of conflict of interest [18] M. Dalamaga, Interplay of adipokines and myokines in cancer pathophysiology:
emerging therapeutic implications, World J. Exp. Med. 3 (2013) 26–33.
[19] S. Raschke, J. Eckel, Adipo-myokines: two sides of the same coin–mediators of in-
None. flammation and mediators of exercise, Mediators Inflamm. 2013 (2013) 320724.
[20] H. Bruunsgaard, Physical activity and modulation of systemic low-level in-
Financial support flammation, J. Leukoc. Biol. 78 (2005) 819–835.
[21] M.A. Nimmo, M. Leggate, J.L. Viana, J.A. King, The effect of physical activity on
mediators of inflammation, Diabetes Obes. Metab. 15 (2013) 51–60.
None. [22] B.K. Pedersen, T.C. Akerström, A.R. Nielsen, C.P. Fischer, Role of myokines in ex-
ercise and metabolism, J. Appl. Physiol. 103 (2007) (1985) 1093–1098.
[23] B.K. Pedersen, C.P. Fischer, Beneficial health effects of exercise—the role of IL-6 as
Appendix A
a myokine, Trends Pharmacol. Sci. 28 (2007) 152–156 PMID:17331593.
[24] B.K. Pedersen, M.A. Febbraio, Muscle as an endocrine organ: focus on muscle-de-
BDNF: brain-derived neurotrophic factor. rived interleukin-6, Physiol. Rev. 88 (2008) 1379–1406.

4
B.B. Díaz et al. Immunology Letters 203 (2018) 1–5

[25] S. Nielsen, B.K. Pedersen, Skeletal muscle as an immunogenic organ, Curr. Opin. [45] B.K. Pedersen, Exercise-induced myokines and their role in chronic diseases, Brain
Pharmacol. 8 (2008) 346–351. Behav. Immun. 25 (2011) 811–816.
[26] A.P. Lightfoot, R.G. Cooper, The role of myokines in muscle health and disease, [46] B.K. Pedersen, The anti-inflammatory effect of exercise: its role in diabetes and
Curr. Opin. Rheumatol. 28 (2016) 661–666. cardiovascular disease control, Essays Biochem. 42 (2006) 105–117.
[27] A. Pinto, D. Di Raimondo, A. Tuttomondo, C. Buttà, G. Milio, G. Licata, Effects of [47] A. Pratesi, F. Tarantini, M. Di Bari, Skeletal muscle: an endocrine organ, Clin. Cases
physical exercise on inflammatory markers of atherosclerosis, Curr. Pharm. Des. 18 Miner. Bone Metab. 10 (2013) 11–14.
(2012) 4326–4349. [48] B.K. Pedersen, Muscles and their myokines, J. Exp. Biol. 214 (2011) 337–346.
[28] L. Vella, M.K. Caldow, A.E. Larsen, D. Tassoni, P.A. Della Gatta, P. Gran, [49] A.S. Arnold, A. Egger, C. Handschin, PGC-1α and myokines in the aging muscle - a
A.P. Russell, D. Cameron-Smith, Resistance exercise increases NF-κB activity in mini-review, Gerontology 57 (2011) 37–43.
human skeletal muscle, Am. J. Physiol. Regul. Integr. Comp. Physiol. 302 (2012) [50] F. Demontis, R. Piccirillo, A.L. Goldberg, N. Perrimon, The influence of skeletal
R667–673. muscle on systemic aging and lifespan, Aging Cell 12 (2013) 943–949.
[29] C. Scheele, S. Nielsen, B.K. Pedersen, ROS and myokines promote muscle adaptation [51] T.C. Hoffmann, C.G. Maher, T. Briffa, C. Sherrington, K. Bennell, J. Alison,
to exercise, Trends Endocrinol. Metab. 20 (2009) 95–99. M.F. Singh, P.P. Glasziou, Prescribing exercise interventions for patients with
[30] B.J. Schoenfeld, Potential mechanisms for a role of metabolic stress in hypertrophic chronic conditions, CMAJ 188 (2016) 510–518.
adaptations to resistance training, Sports Med. 43 (2013) 179–194. [52] A.M. Petersen, B.K. Pedersen, The anti-inflammatory effect of exercise, J. Appl.
[31] K. Walsh, Adipokines, myokines and cardiovascular disease, Circ. J. 73 (2009) Physiol. 98 (2005) (1985) 1154–1162.
13–18. [53] M. Pal, M.A. Febbraio, M. Whitham, From cytokine to myokine: the emerging role
[32] N.H. Yeo, J. Woo, K.O. Shin, J.Y. Park, S. Kang, The effects of different exercise of interleukin-6 in metabolic regulation, Immunol. Cell Biol. 92 (2014) 331–339.
intensity on myokine and angiogenesis factors, J. Sports Med. Phys. Fitness 52 [54] K. Karstoft, B.K. Pedersen, Exercise and type 2 diabetes: focus on metabolism and
(2012) 448–454. inflammation, Immunol. Cell Biol. 94 (2016) 146–150.
[33] L.F. Ferreira, M.B. Reid, Muscle-derived ROS and thiol regulation in muscle fatigue, [55] L.Q. Jiang, D.E. Duque-Guimaraes, U.F. Machado, J.R. Zierath, A. Krook, Altered
J. Appl. Physiol. 104 (2008) (1985) 853–860. response of skeletal muscle to IL-6 in type 2 diabetic patients, Diabetes 62 (2012)
[34] T.W. Balon, K.K. Yerneni, Redox regulation of skeletal muscle glucose transport, 355–361.
Med. Sci. Sports Exerc. 33 (2001) 382–385. [56] Y. Liu, S. Chewchuk, C. Lavigne, S. Brûlé, G. Pilon, V. Houde, A. Xu, A. Marette,
[35] Z. Stránská, Š. Svačina, Myokines-muscle tissue hormones, Vnitr. Lek. 61 (2015) G. Sweeney, Functional significance of skeletal muscle adiponectin production,
365–368. changes in animal models of obesity and diabetes, and regulation by rosiglitazone
[36] B.K. Pedersen, IL-6 signalling in exercise and disease, Biochem. Soc. Trans. 35 treatment, Am. J. Physiol. Endocrinol. Metab. 297 (2009) E657–E664.
(2007) 1295–1297. [57] J.S. Hansen, X. Zhao, M. Irmler, X. Liu, M. Hoene, M. Scheler, Y. Li, J. Beckers,
[37] K. Ostrowski, T. Rohde, M. Zacho, S. Asp, B.K. Pedersen, Evidence that interleukin-6 M. Hrabĕ de Angelis, H.U. Häring, B.K. Pedersen, R. Lehmann, G. Xu, P. Plomgaard,
is produced in human skeletal muscle during prolonged running, J. Physiol. 508 C. Weigert, Type 2 diabetes alters metabolic and transcriptional signatures of glu-
(1998) 949–953. cose and amino acid metabolism during exercise and recovery, Diabetologia 58
[38] A. Steensberg, C.P. Fischer, C. Keller, K. Møller, B.K. Pedersen, IL-6 enhances (2015) 1845–1854.
plasma IL-1ra, IL-10, and cortisol in humans, Am. J. Physiol. Endocrinol. Metab. [58] P. Plomgaard, P.A. Halban, K. Bouzakri, Bimodal impact of skeletal muscle on
285 (2003) E433–E437. pancreatic β-cell function in health and disease, Diabetes Obes. Metab. 14 (2012)
[39] A. Steensberg, G. van Hall, T. Osada, M. Sacchetti, B. Saltin, P.B. Klarlund, 78–84.
Production of interleukin-6 in contracting human skeletal muscles can account for [59] R. Gopurappilly, R. Bhonde, Can multiple intramuscular injections of mesenchymal
the exercise-induced increase in plasma interleukin-6, J. Physiol. 529 (2000) stromal cells overcome insulin resistance offering an alternative mode of cell
237–242. therapy for type 2 diabetes? Med. Hypotheses 78 (2012) 393–395.
[40] A. Steensberg, M.A. Febbraio, T. Osada, P. Schjerling, G. van Hall, B. Saltin, [60] M.L. Mizgier, M. Casas, A. Contreras-Ferrat, P. Llanos, J.E. Galgani, Potential role of
B.K. Pedersen, Interleukin-6 production in contracting human skeletal muscle is skeletal muscle glucose metabolism on the regulation of insulin secretion, Obes.
influenced by pre-exercise muscle glycogen content, J. Physiol. 537 (2001) Rev. 15 (2014) 587–597.
633–639. [61] J.H. Yoon, P. Song, J.H. Jang, D.K. Kim, S. Choi, J. Kim, J. Ghim, D. Kim, S. Park,
[41] N. Hiscock, M.H. Chan, T. Bisucci, I.A. Darby, M.A. Febbraio, Skeletal myocytes are H. Lee, D. Kwak, K. Yea, D. Hwang, P.G. Suh, S.H. Ryu, Proteomic analysis of tumor
a source of interleukin-6 mRNA expression and protein release during contraction: necrosis factor-alpha (TNF-α)-induced L6 myotube secretome reveals novel TNF-α-
evidence of fiber type specificity, FASEB J. 18 (2004) 992–994. dependent myokines in diabetic skeletal muscle, J. Proteome Res. 10 (2011)
[42] M. Whitham, M.H. Chan, M. Pal, V.B. Matthews, O. Prelovsek, S. Lunke, A. El-Osta, 5315–5325.
H. Broenneke, J. Alber, J.C. Brüning, F.T. Wunderlich, G.I. Lancaster, [62] F.B. Benatti, B.K. Pedersen, Exercise as an anti-inflammatory therapy for rheumatic
M.A. Febbraio, Contraction-induced interleukin-6 gene transcription in skeletal diseases-myokine regulation, Nat. Rev. Rheumatol. 11 (2015) 86–97.
muscle is regulated by c-Jun terminal kinase/activator protein-1, J. Biol. Chem. 287 [63] K. Sharif, A. Watad, N.L. Bragazzi, M. Lichtbroun, H. Amital, Y. Shoenfeld, Physical
(2012) 10771–10779. activity and autoimmune diseases: get moving and manage the disease,
[43] M.A. Febbraio, N. Hiscock, M. Sacchetti, C.P. Fischer, B.K. Pedersen, Interleukin-6 is Autoimmun. Rev. 17 (2018) 53–72.
a novel factor mediating glucose homeostasis during skeletal muscle contraction, [64] J. Bilski, Al. Mazur-Bialy, M. Wierdak, T. Brzozowski, The impact of physical ac-
Diabetes 53 (2004) 1643–1648. tivity and nutrition on inflammatory bowel disease: the potential role of cross talk
[44] N. Mathur, B.K. Pedersen, Exercise as a mean to control low-grade systemic in- between adipose tissue and skeletal muscle, J. Physiol. Pharmacol. 64 (2013)
flammation, Mediators Inflamm. 2008 (2008) 109502. 143–155.