The concentration of plasma interleukin (IL)-6 increases during physical exercise and recent research identifies skeletal muscle as an endocrine organ, which is the major source of the exercise-induced increase in IL-6. We have identified muscle-derived IL-6 as the first muscle-derived cytokine.
Myokines represent the link from working muscle to other organs, such as the adipose tissue, the liver and vascular compartments. We suggest that myokines may provide an explanation of how regular muscle activity protects against Type 2 diabetes, atherosclerosis and dementia.
Regular exercise offers protection against all-cause mortality, primarily by protection against atherosclerosis, Type 2 diabetes, colon cancer and breast cancer Citation[1]. In addition, physical training is effective in the treatment of patients with ischemic heart disease Citation[2], heart failure Citation[3] and Type 2 diabetes Citation[4]. Although the evidence is less clear, regular physical activity has been shown to protect against depression Citation[5] and is associated with a reduced risk of dementia Citation[6,7].
It is discussed how contracting skeletal muscles mediate metabolic and physiological effects of benefits on health.
For most of the last century, researchers have searched for a muscle contraction-induced factor that could mediate some of the exercise-induced changes in other organs Citation[8]. For years, the search for the stimulus that initiates and maintains this change of excitability or sensibility of the regulating centers in exercise has been ongoing. Owing to the lack of more precise knowledge, it has been called the work stimulus, the work factor or the exercise factor Citation[9]. The concept of an exercise factor builds on the fact that contracting skeletal muscle mediates metabolic and physiological responses in other organs, which are not mediated by nerve impulses. The signaling pathways from contracting skeletal muscles to other organs do not involve the nervous system, as demonstrated by the fact that electrical stimulation of paralyzed muscles in spinal cord-injured patients with no afferent and efferent nerve impulses induces, in essence, the same physiological changes as in intact human beings. Thus, it has been clear that contracting skeletal muscles communicate to other organs via humoral factors (exercise factors) that are produced and released into the circulation during physical activity. Such factors might directly or indirectly induce functional changes in other organs, such as adipose tissue, the liver, the cardiovascular system and the brain. Thus, exercise factors may contribute to mediating the health beneficial effects of exercise. We identify IL-6 as an exercise factor and suggest that IL-6 and other cytokines, which are produced and released by skeletal muscles and exert their effects on other organs of the body, should be named myokines Citation[9,10].
Exercise & IL-6
Plasma IL-6 increases in an exponential fashion with exercise and is related to exercise intensity, duration, the mass of muscle recruited and endurance capacity Citation[9,11–13]. These review articles summarize the following findings: IL-6 mRNA is upregulated in contracting skeletal muscle and the transcriptional rate of the IL-6 gene is markedly enhanced by exercise. In addition, the IL-6 protein is expressed in contracting muscle fibers and IL-6 is released from skeletal muscle during exercise. Studies have reported that carbohydrate ingestion attenuates elevations in plasma IL-6 during both running and cycling. Pre-exercise intramuscular glycogen content appears to be an important stimulus for IL-6 gene transcription and muscle IL-6 is further regulated by an autocrine mechanism. Besides skeletal muscle, other tissues may also contribute to the systemic increase in IL-6 concentration during exercise. Studies have demonstrated that monocytes are not major contributors to the IL-6 response to exercise Citation[9,11–13], but that IL-6, to a minor degree, is produced from adipose tissue, peritendon tissue and the brain.
IL-6: a role in glucose & lipid metabolism?
Skeletal muscle contraction is a powerful stimulus for glucose disposal and a key question in exercise physiology has been how glucose homeostasis is regulated during exercise. The glucose uptake in contracting skeletal muscle would lead to hypoglycemia if the endogenous glucose production (EGP) and glucose output from the liver was not stimulated during exercise. Regulation of the contraction-induced increase in EGP has been the focus of a vast number of studies over the past 40 years. In general, it is accepted that during exercise at a moderate intensity, glucoregulation is mediated primarily by an increase in the portal venous glucagon:insulin ratio, but studies have been unable to fully elucidate the precise mediator(s) of contraction-induced EGP. As far back as the 1960s, it was suggested that muscle cells possess a humoral component and, since this time, many studies have concluded that an as-yet unidentified factor released from contracting muscle cells may contribute to the increase in hepatic glucose production. We recently tested the hypothesis that IL-6 is involved in mediating EGP during exercise. Humans performed 2 h of bicycle exercise on three separate occasions at a relatively high intensity or at a low intensity with or without an infusion of recombinant human IL-6 that matched the circulating concentration of IL-6 seen during high-intensity exercise Citation[14]. Using stable isotopes we observed that, throughout exercise at the low intensity with IL-6 infusion, glucose appearance and disappearance was higher than exercise at the low intensity without IL-6. Moreover, glucoregulatory hormones were identical when comparing these trials. These data suggest that, although IL-6 has no effect on EGP at resting conditions, it is involved in mediating glucose homeostasis during exercise.
IL-6 influences glucose homeostasis during exercise and provides potential new insights into factors that mediate glucose production and disposal, implicating IL-6 in the so-called work factor.
However, whereas IL-6 release from skeletal muscles is attenuated by glucose ingestion Citation[9,11–13], the brain shows an inverse response. Thus, the brain contributes to the elevated level of circulating IL-6 during carbohydrate administration, while hypoglycemia abolishes the cerebral IL-6 release Citation[15]. Therefore, exercise-induced IL-6 production and release from the brain appears to have a different function from muscle-derived IL-6.
There is strong evidence that IL-6 may also affect lipid metabolism. Recently, studies have demonstrated that IL-6 infusion or incubation results in lipolysis and fat oxidation both in humans in vivo and in skeletal muscle in vitro. In accordance with this, IL-6-deficient mice developed mature-onset obesity Citation[9,11–13].
Anti-inflammatory effects of IL-6
The anti-inflammatory profile of IL-6 represents yet another important biological effect of this cytokine. Both an acute bout of exercise as well as recombinant human (rh)IL-6 infusion inhibits the endotoxin-induced increase in circulating levels of tumor necrosis factor (TNF)-α in healthy humans Citation[16]. TNF-α has direct inhibitory effects on insulin signaling Citation[17] and the ability of IL-6 to inhibit TNF-α production may represent a mechanism whereby exercise enhances insulin sensitivity. Given that several chronic disorders, such as cardiovascular diseases, Type 2 diabetes, dementia and depression, are associated with chronic low-grade systemic inflammation, the anti-inflammatory effects of IL-6 may represent a mechanism whereby exercise protects against these disorders Citation[18].
Conclusion
Regular exercise offers primary and secondary protection against chronic diseases, such as cardiovascular diseases, Type 2 diabetes, dementia and depression. The long-term effect of exercise may, to some extent, be ascribed to the anti-inflammatory response elicited by an acute bout of exercise, which is partly mediated by muscle-derived IL-6. Recently, we proposed that IL-6 and other cytokines, which are produced and released by skeletal muscles and exert their effects in other organs of the body, should be named myokines Citation[9]. This concept may be extended to explain not only the effect of exercise on metabolism, but also how regular muscle activity influences mood, performance and cognitive function.
Acknowledgements
The Centre of Inflammation and Metabolism is supported by a grant from the Danish National Research Foundation (#02–512–55). The study was further supported by the Danish Medical Research Council (#22–01–009) and the Commission of the European Communities (Contract No LSHM-CT-2004–005272 EXGENESIS).
References
- Blair SN, Cheng Y, Holder JS. Is physical activity or physical fitness more important in defining health benefits? Med. Sci. Sports Exerc.33(6 Suppl.), S379–S399 (2001).
- Bedard S, Marcotte B, Marette A. Cytokines modulate glucose transport in skeletal muscle by inducing the expression of inducible nitric oxide synthase. Biochem. J.15(325), 487–493 (1997).
- Piepoli MF, Davos C, Francis DP, Coats AJ. Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH). Br. Med. J.328(7433), 189 (2004).
- Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA286(10), 1218–1227 (2001).
- Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch. Neurol.58(3), 498–504 (2001).
- Larson EB, Wang L, Bowen JD et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann. Intern. Med.144(2), 73–81 (2006).
- Podewils LJ, Guallar E, Kuller LH et al. Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am. J. Epidemiol.161(7), 639–651 (2005).
- Winocour PH, Durrington PN, Bhatnagar D et al. A cross-sectional evaluation of cardiovascular risk factors in coronary heart disease associated with type 1 (insulin-dependent) diabetes mellitus. Diabetes Res. Clin. Pract.18(3), 173–184 (1992).
- Pedersen BK, Steensberg A, Fischer C et al. Searching for the exercise factor – is IL-6 a candidate. J. Musc. Res. Cell Motility24(2–3), 113–119 (2003).
- Pedersen BK, Steensberg A, Fischer C et al. The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor? Proc. Nutr. Soc.63(2), 263–267 (2004).
- Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regulation, integration and adaption. Physiol. Rev.80, 1055–1081 (2000).
- Pedersen BK, Steensberg A, Schjerling P. Muscle-derived interleukin-6: possible biological effects. J. Physiol. (Lond.)536(Pt 2), 329–337 (2001).
- Febbraio MA, Pedersen BK. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J.16(11), 1335–1347 (2002).
- Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes53(7), 1643–1648 (2004).
- Nybo L, Moller K, Pedersen BK, Nielsen B, Secher NH. Association between fatigue and failure to preserve cerebral energy turnover during prolonged exercise. Acta Physiol. Scand.179(1), 67–74 (2003).
- Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-α production in humans. FASEB J.17(8), 884–886 (2003).
- Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science271(5249), 665–668 (1996).
- Petersen EW, Pedersen BK. The anti-inflammatory effect of exercise. J. Appl. Physiol.98(4), 1154–1162 (2005).