Interleukin-6 modifies mRNA expression in mouse skeletal muscle (original) (raw)
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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,
AJP: Endocrinology and Metabolism, 2004
Contracting skeletal muscle expresses large amounts of IL-6. Because 1) IL-6 mRNA expression in contracting skeletal muscle is enhanced by low muscle glycogen content, and 2) IL-6 increases lipolysis and oxidation of fatty acids, we hypothesized that regular exercise training, associated with increased levels of resting muscle glycogen and enhanced capacity to oxidize fatty acids, would lead to a less-pronounced increase of skeletal muscle IL-6 mRNA in response to acute exercise. Thus, before and after 10 wk of knee extensor endurance training, skeletal muscle IL-6 mRNA expression was determined in young healthy men ( n = 7) in response to 3 h of dynamic knee extensor exercise, using the same relative workload. Maximal power output, time to exhaustion during submaximal exercise, resting muscle glycogen content, and citrate synthase and 3-hydroxyacyl-CoA dehydrogenase enzyme activity were all significantly enhanced by training. IL-6 mRNA expression in resting skeletal muscle did not ...
Searching for the exercise factor: Is IL-6 a candidate?
Journal of Muscle Research and Cell Motility, 2003
For years the search for the stimulus that initiates and maintains the change of excitability or sensibility of the regulating centers in exercise has been progressing. For lack of more precise knowledge, it has been called the 'work stimulus', 'the work factor' or 'the exercise factor'. In other terms, one big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. Here we discuss the possibility that interleukin-6 (IL-6) could mediate some of the health beneficial effects of exercise. In resting muscle, the IL-6 gene is silent, but it is rapidly activated by contractions. The transcription rate is very fast and the fold changes of IL-6 mRNA is marked. IL-6 is released from working muscles into the circulation in high amounts. The IL-6 production is modulated by the glycogen content in muscles, and IL-6 thus works as an energy sensor. IL-6 exerts its effect on adipose tissue, inducing lipolysis and gene transcription in abdominal subcutaneous fat and increases whole body lipid oxidation. Furthermore, IL-6 inhibits low-grade TNF-a-production and may thereby inhibit TNF-a-induced insulin resistance and atherosclerosis development. We propose that IL-6 and other cytokines, which are produced and released by skeletal muscles, exerting their effects in other organs of the body, should be named 'myokines'.
AJP: Cell Physiology, 2007
Skeletal muscle cells have been established as significant producers of IL-6 during exercise. This IL-6 production is discussed as one possible mediator of the beneficial effects of physical activity on glucose and fatty acid metabolism. IL-6 itself could be the exercise-related factor that upregulates and maintains its own production. We investigated this hypothesis and the underlying molecular mechanism in cultured C2C12 cells. IL-6 led to a rapid and prolonged increase in IL-6 mRNA, which was also found in human myotubes. Because IL-6 has been shown to activate AMP-activated kinase (AMPK), we studied whether, in turn, activated AMPK induces IL-6 expression. Pharmacological activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside upregulated IL-6 mRNA expression, which was blocked by knockdown of AMPK α1 and α2 using small, interfering RNA (siRNA) oligonucleotides. However, the effect of IL-6 was shown to be independent of AMPK, since the siRNA approach silencin...
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...
AMPK activity is diminished in tissues of IL6 knockout mice: the effect of exercise
Biochemical and Biophysical Research Communications, 2004
Following exercise, AMP-activated protein kinase (AMPK) activity is increased several fold in rat liver and adipose tissue as well as muscle; however, the mechanism by which this occurs is not known. Interleukin-6 (IL-6) is released from muscle in large amounts during and after sustained physical activity resulting in up to 100-fold increases in its plasma concentration, from 1-2 ng/ml to 50-100 ng/ml. We report here that incubation with IL-6 (30-120 ng/ml) increases the phosphorylation of AMPK (an indicator of its activation) and that of its target molecule, acetyl CoA carboxylase (ACC), in both extensor digitorum longus muscle and cultured F422a adipocytes. To assess more directly whether IL-6 regulates AMPK in vivo during exercise, measurements were carried out in skeletal muscle, liver, and adipose tissue of 3-month-old IL-6 knockout (IL-6 À=À ) and C57 black control mice. In agreement with previous studies in the rat, in control mice P-AMPK and P-ACC abundance was increased by 30-150% in the three tissues in response to exercise with the greatest increases in skeletal muscle. In contrast, in IL-6 À=À mice, we found that the abundance of both P-AMPK and P-ACC was lower (60-90%) in muscle and adipose tissue at rest. Also the absolute increases in P-AMPK caused by exercise were diminished compared to those in control mice, although percentage increases were similar. In liver, decreases in P-AMPK and P-ACC in the IL-6 À=À mice were more modest and the increases in their abundance caused by exercise were indistinguishable from those of control mice. The results indicate that IL-6 can activate AMPK in muscle and adipose tissue, and that this contributes to, but does not fully account for, the increase in AMPK activity in these tissues in response to exercise. They also suggest that a genetic lack of IL-6 is associated with a decrease in AMPK activity.
The FASEB Journal, 2001
In humans, the plasma interleukin 6 (IL-6) concentration increases dramatically during lowintensity exercise. Measurements across the working limb indicate that skeletal muscle is the source of IL-6 production. To determine whether energy availability influences the regulation of IL-6 expression during prolonged exercise, six male subjects completed two trials consisting of 180 min of two-legged dynamic knee extensor with either normal or low (~60% of control) preexercise muscle glycogen levels. Increases in plasma IL-6 during exercise were significantly higher (P<0.05) in the low-glycogen (16-fold) trial verses the control (10-fold) trial. Transcriptional activation of the IL-6 gene in skeletal muscle was also higher in the lowglycogen trial; it increased by about 40-fold after 90 min of exercise and about 60-fold after 180 min of exercise. Muscle IL-6 mRNA followed a similar but delayed pattern, increasing by more than 100-fold in the low-glycogen trial and by about 30-fold in the control trial. These data demonstrate that exercise activates transcription of the IL-6 gene in working skeletal muscle, a response that is dramatically enhanced when glycogen levels are low. These findings also support the hypothesis that IL-6 may be produced by contracting myofibers when glycogen levels become critically low as a means of signaling the liver to increase glucose production.
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.