Searching for the exercise factor: Is IL-6 a candidate? (original) (raw)
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Beneficial health effects of exercise – the role of IL-6 as a myokine
Trends in Pharmacological Sciences, 2007
It is not clear how contracting skeletal muscles mediate the numerous and diverse metabolic and physiological effects that are beneficial for health. Researchers have searched for a muscle-contraction-induced factor-an 'exercise factor'-that mediates some of the exercise effects in other tissues such as the liver and adipose tissue. In our search for such a factor, we encountered the cytokine interleukin (IL)-6, which is produced by contracting muscles and released into the blood. We propose that muscle-derived IL-6 meets the criteria of an exercise factor and that such classes of cytokine should be named 'myokines'. The discovery of contracting muscle as a cytokine-producing organ creates a new paradigm: skeletal muscle as an endocrine organ. By contracting, it stimulates the production and release of myokines that can influence metabolism in tissue and organs. Newly identified myokines and their receptors could serve as targets in the treatment of metabolic disorders and other diseases.
The role of interleukin-6 as a signalizer in different tissues during physical exercise
Fitness & Performance Journal
The big challenge for exercise physiologists has been to determine how the muscles signalize to the central nervous system and to the peripheral organs, during physical exercise. The search for knowledge about the signalizers produced during exercise, the relations between the muscle, brain and other tissues increased considerably. The interleukin-6 (IL-6) and other cytokines, which are produced and released by skeletal muscle, may exert their regulatory effects on the adipose tissue, brain, cardiovascular system and the liver, receiving the denomination of myokines. Additionally, the very adipose tissue, as well as the brain, produces IL-6 that possibly acts as a signalizer between these tissues, exerting influence in the metabolic system and in the fatigue during exercise.
IL-6 regulates exercise and training-induced adaptations in subcutaneous adipose tissue in mice
Acta Physiologica, 2012
Aim: The aim of this study was to test the hypothesis that IL-6 regulates exercise-induced gene responses in subcutaneous adipose tissue in mice. Methods: Four-month-old male IL-6 whole body knockout (KO) mice and C57B wild-type (WT) mice performed 1 h of treadmill exercise, where subcutaneous adipose tissue (AT) was removed either immediately after, 4 h or 10 h after exercise as well as from mice not running acutely. Moreover, AT was sampled at resting conditions after 5 weeks of exercise training. Results: AT leptin mRNA decreased immediately after a single running exercise bout in both genotypes and returned to baseline within 10 h of recovery in IL-6 KO mice, but not WT mice. Leptin mRNA content decreased in WT and increased in IL-6 KO mice with training, but without significant alterations in leptin protein. Acute exercise induced a decrease in the AT TNFa mRNA content in WT, but not in IL-6-KO mice, while training lowered resting levels of TNFa mRNA in both genotypes. In addition, an exercise-induced decline in AT PPARc mRNA content was absent in IL-6 KO mice and in line training increased PPARc mRNA only in IL-6 KO mice. Conclusion: The present findings indicate a role of IL-6 in regulating exercise-and training-induced leptin and PPARc expression in adipose tissue. In addition, while IL-6 is required for TNF-a mRNA reduction in response to acute exercise, IL-6 does not appear to be mandatory for anti-inflammatory effects of exercise training in adipose tissue.
Journal of Applied Physiology, 2005
The cytokine interleukin-6 (IL-6) exerts it actions via the IL-6 receptor (IL-6R) in conjunction with the ubiquitously expressed gp130 receptor. IL-6 is tightly regulated in response to exercise, being affected by factors such as exercise intensity and duration, as well as energy availability. Although the IL-6 response to exercise has been extensively studied, little is known about the regulation of the IL-6R response. In the present study, we aimed to investigate the effect of exercise, training, and glycogen availability, factors known to affect IL-6, on the regulation of gene expression of the IL-6R in human skeletal muscle. Human subjects performed either 10 wk of training with an acute exercise bout before and after the training period, or a low-glycogen vs. normal-glycogen acute exercise trial. The IL-6R mRNA response was evaluated in both trials. In response to acute exercise, an increase in IL-6R mRNA levels was observed. Neither training nor intramuscular glycogen levels had an effect on the IL-6R mRNA response to exercise. However, after 10 wk of training, the skeletal muscle expressed a higher mRNA level of IL-6R compared with before training. The present study demonstrated that the IL-6R gene expression levels in skeletal muscle are increased in response to acute exercise, a response that is very well conserved, being affected by neither training status nor intramuscular glycogen levels, as opposed to IL-6. However, after the training period, IL-6R mRNA production was increased in skeletal muscle, suggesting a sensitization of skeletal muscle to IL-6 at rest. interleukin-6 receptor CYTOKINES EXERT THEIR ACTIONS via specific receptors, which by themselves can be regulated via local and systemic factors. One of these cytokine and receptor systems is the IL-6/IL-6 receptor (IL-6R) system. IL-6 has various roles in immune function, but it is also produced in response to acute exercise, where it serves a metabolic role. Thus an infusion of IL-6 results in increased lipolysis and oxidation rate (32) and increases hepatic glucose production during exercise (6). IL-6 also increases the insulin-stimulated glucose uptake in myocytes, indicating an autocrine role on the skeletal muscle (2). The expression of IL-6 is tightly regulated during an acute exercise bout. Its regulation in skeletal muscle depends on exercise intensity and duration, as well as energy availability such as intramuscular glycogen and blood glucose levels (7,
Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects
Pflügers Archiv : European journal of physiology, 2003
Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the exercise-induced increase in plasma IL-6. The transcription rate for IL-6 in muscle nuclei isolated from muscle biopsies during exercise is very high and is enhanced further when muscle glycogen content is low. Furthermore, cultured human primary muscle cells can increase IL-6 mRNA when incubated with the calcium ionophore ionomycin and it is likely that myocytes produce IL-6 in response to muscle contraction. The biological roles of muscle-derived IL-6 have been investigated in studies in which human recombinant IL-6 was infused in healthy volunteers to mimic closely the IL-6 concentrations observed during prolonged exercise. Using stable isotopes, we have demonstrated that physiological concentrations of IL-6 induce lipolysis. Although we have yet to determine the precise biological action of muscle-derived IL-6, our data support the hypothesis that the role of IL-6 released from contractin...
Interleukin-6 modifies mRNA expression in mouse skeletal muscle
Acta Physiologica, 2011
Aim: The aim of this study was to test the hypothesis that interleukin (IL)-6 plays a role in exercise-induced peroxisome proliferator-activated receptor c co-activator (PGC)-1a and tumor necrosis factor (TNF)-a mRNA responses in skeletal muscle and to examine the potential IL-6-mediated AMP-activated protein kinase (AMPK) regulation in these responses. Methods: Whole body IL-6 knockout (KO) and wildtype (WT) male mice (4 months of age) performed 1 h treadmill exercise. White gastrocnemius (WG) and quadriceps (Quad) muscles were removed immediately (0¢) or 4 h after exercise and from mice not run acutely. Results: Acute exercise reduced only in WT muscle glycogen concentration to 55 and 35% (P < 0.05) of resting level in Quad and WG respectively. While AMPK and Acetyl CoA carboxylase (ACC) phosphorylation increased 1.3-fold (P < 0.05) in WG and twofold in Quad immediately after exercise in WT mice, no change was detected in WG in IL-6 KO mice. The PGC-1a mRNA content was in resting WG 1.8-fold higher (P < 0.05) in WT mice than in IL-6 KO mice. Exercise induced a delayed PGC-1a mRNA increase in Quad in IL-6 KO mice (12-fold at 4 h) relative to WT mice (fivefold at 0¢). The TNF-a mRNA content was in resting Quad twofold higher (P < 0.05) in IL-6 KO than in WT, and WG TNF-a mRNA increased twofold (P < 0.05) immediately after exercise only in IL-6 KO. Conclusion: In conclusion, IL-6 affects exercise-induced glycogen use, AMPK signalling and TNF-a mRNA responses in mouse skeletal muscle.
Immunohistochemical detection of interleukin-6 in human skeletal muscle fibers following exercise
The FASEB Journal, 2003
Interleukin-6 (IL-6) is produced by many different cell types. Human skeletal muscles produce and release high amounts of IL-6 during exercise; however, the cell source of origin in the muscle is not known. Therefore, we studied the protein expression of IL-6 by immunohistochemistry in human muscle tissue from biopsies obtained at time points 0, 3, 4.5, 6, 9, and 24 h in relation to 3 h of bicycle exercise performed by healthy young males (n=12) and in resting controls (n=6). The IL-6 expression was clearly increased after exercise and remained high even by 24 h, relative to preexercise or resting individuals. The IL-6 immunostainings of skeletal muscle cells were homogeneous and without difference between muscle fiber types. The IL-6 mRNA peaked immediately after the exercise, and, in accordance, the IL-6 protein expression within muscle cells was most pronounced around 3 h post-exercise. However, the finding that plasma IL-6 concentration peaked in the end of exercise indicates a high turnover of muscle-derived IL-6. In conclusion, the finding of marked IL-6 protein expression exclusively within skeletal muscle fibers following exercise demonstrates that skeletal muscle fibers of all types are the dominant cell source of exercise-induced release of IL-6 from working muscle.
Interleukin-6 in acute exercise and training: what is the biological relevance?
Exercise immunology review, 2006
It is now recognized that contracting skeletal muscle may synthesize and release interleukin-6 (IL-6) into the interstitium as well as into the systemic circulation in response to a bout of exercise. Although several sources of IL-6 have been demonstrated, contracting muscles contributes to most of the IL-6 present in the circulation in response to exercise. The magnitude of the exercise-induced IL-6 response is dependent on intensity and especially duration of the exercise, while the mode of exercise has little effect. Several mechanisms may link muscle contractions to IL-6 synthesis: Changes in calcium homeostasis, impaired glucose availability, and increased formation of reactive oxygen species (ROS) are all capable of activating transcription factors known to regulate IL-6 synthesis. Via its effects on liver, adipose tissue, hypothalamic-pituitary-adrenal (HPA) axis and leukocytes, IL-6 may modulate the immunological and metabolic response to exercise. However, prolonged exercis...