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DOI: 10.1055/s-0033-1353147
Exercise Sensitizes Skeletal Muscle to Extracellular ATP for IL-6 Expression in Mice
Publication History
accepted after revision 04 July 2013
Publication Date:
10 September 2013 (online)
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Abstract
Active skeletal muscle synthesizes and releases interleukin-6 (IL-6), which plays important roles in the organism’s adaptation to exercise. Autocrine/paracrine ATP signaling has been shown to modulate IL-6 expression. The aim of this study was to determine whether a period of physical activity modifies the ATP-induced IL-6 expression. BalbC mice were either subject to 5 weeks voluntary wheel running (VA) or kept sedentary (SED). Flexor digitorum brevis muscles were dissected, stimulated with different ATP concentrations (0-100 μM) and IL-6 mRNA levels were measured using qPCR. ATP evoked a concentration-dependent rise in IL-6 mRNA in both SED and VA mice. VA mice however, had significantly higher ATP sensitivity (pD2 pharmacological values: VA=5.58±0.02 vs. SED=4.95±0.04, p<0.05). Interestingly, in VA mice we observed a positive correlation between the level of physical activity and the IL-6 mRNA increase following fiber stimulation with 10 μM ATP. In addition, there were lower P2Y2- and higher P2Y14-receptor mRNA levels in skeletal muscles of VA compared to SED mice, showing plasticity of nucleotide receptors with exercise. These results suggest that exercise increases skeletal muscle ATP sensitivity, a response dependent on the level of physical activity performed. This could have an important role in the mechanisms controlling skeletal muscle adaptation to exercise and training.
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References
- 1 Akerstrom TC, Krogh-Madsen R, Petersen AM, Pedersen BK. Glucose ingestion during endurance training in men attenuates expression of myokine receptor. Exp Physiol 2009; 94: 1124-1131
- 2 Al-Khalili L, Bouzakri K, Glund S, Lonnqvist F, Koistinen HA, Krook A. Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle. Mol Endocrinol 2006; 20: 3364-3375
- 3 Allen DL, Harrison BC, Maass A, Bell ML, Byrnes WC, Leinwand LA. Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J Appl Physiol 2001; 90: 1900-1908
- 4 Borno A, Ploug T, Bune LT, Rosenmeier JB, Thaning P. Purinergic receptors expressed in human skeletal muscle fibres. Purinergic Signal 2012; 8: 255-264
- 5 Burnstock G. Purinergic signaling: Its unpopular beginning, its acceptance and its exciting future. Bioessays 2012; 34: 218-225
- 6 Buvinic S, Almarza G, Bustamante M, Casas M, Lopez J, Riquelme M, Saez JC, Huidobro-Toro JP, Jaimovich E. ATP released by electrical stimuli elicits calcium transients and gene expression in skeletal muscle. J Biol Chem 2009; 284: 34490-34505
- 7 Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Pedersen BK, Febbraio MA. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 2006; 55: 2688-2697
- 8 Carrasco MA, Riveros N, Rios J, Muller M, Torres F, Pineda J, Lantadilla S, Jaimovich E. Depolarization-induced slow calcium transients activate early genes in skeletal muscle cells. Am J Physiol 2003; 284: C1438-C1447
- 9 Casas M, Figueroa R, Jorquera G, Escobar M, Molgo J, Jaimovich E. IP(3)-dependent, post-tetanic calcium transients induced by electrostimulation of adult skeletal muscle fibers. J Gen Physiol 2010; 136: 455-467
- 10 Coffey VG, Hawley JA. The molecular bases of training adaptation. Sports Med 2007; 37: 737-763
- 11 Croft L, Bartlett JD, MacLaren DP, Reilly T, Evans L, Mattey DL, Nixon NB, Drust B, Morton JP. High-intensity interval training attenuates the exercise-induced increase in plasma IL-6 in response to acute exercise. Appl Physiol Nutr Metab 2009; 34: 1098-1107
- 12 Davidson SR, Burnett M, Hoffman-Goetz L. Training effects in mice after long-term voluntary exercise. Med Sci Sports Exerc 2006; 38: 250-255
- 13 De Bono JP, Adlam D, Paterson DJ, Channon KM. Novel quantitative phenotypes of exercise training in mouse models. Am J Physiol 2006; 290: R926-R934
- 14 Dumke CL, Rhodes JS, Garland Jr T, Maslowski E, Swallow JG, Wetter AC, Cartee GD. Genetic selection of mice for high voluntary wheel running: effect on skeletal muscle glucose uptake. J Appl Physiol 2001; 91: 1289-1297
- 15 Eltit JM, Hidalgo J, Liberona JL, Jaimovich E. Slow calcium signals after tetanic electrical stimulation in skeletal myotubes. Biophys J 2004; 86: 3042-3051
- 16 Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 2004; 53: 1643-1648
- 17 Fischer CP, Plomgaard P, Hansen AK, Pilegaard H, Saltin B, Pedersen BK. Endurance training reduces the contraction-induced interleukin-6 mRNA expression in human skeletal muscle. Am J Physiol 2004; 287: E1189-E1194
- 18 Glund S, Deshmukh A, Long YC, Moller T, Koistinen HA, Caidahl K, Zierath JR, Krook A. Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle. Diabetes 2007; 56: 1630-1637
- 19 Gray SR, Ratkevicius A, Wackerhage H, Coats P, Nimmo MA. The effect of interleukin-6 and the interleukin-6 receptor on glucose transport in mouse skeletal muscle. Exp Physiol 2009; 94: 899-905
- 20 Harrison BC, Bell ML, Allen DL, Byrnes WC, Leinwand LA. Skeletal muscle adaptations in response to voluntary wheel running in myosin heavy chain null mice. J Appl Physiol 2002; 92: 313-322
- 21 Harriss DJ, Atkinson G. Update – Ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
- 22 Hellsten Y, Maclean D, Radegran G, Saltin B, Bangsbo J. Adenosine concentrations in the interstitium of resting and contracting human skeletal muscle. Circulation 1998; 98: 6-8
- 23 Jaimovich E, Reyes R, Liberona JL, Powell JA. IP(3) receptors, IP(3) transients, and nucleus-associated Ca(2+) signals in cultured skeletal muscle. Am J Physiol 2000; 278: C998-C1010
- 24 Jorquera G, Altamirano F, Contreras-Ferrat A, Almarza G, Buvinic S, Jacquemond V, Jaimovich E, Casas M. Cav1.1 controls frequency-dependent events regulating adult skeletal muscle plasticity. J Cell Sci 2013;
- 25 Juretic N, Garcia-Huidobro P, Iturrieta JA, Jaimovich E, Riveros N. Depolarization-induced slow Ca2+ transients stimulate transcription of IL-6 gene in skeletal muscle cells. Am J Physiol 2006; 290: C1428-C1436
- 26 Juretic N, Urzua U, Munroe DJ, Jaimovich E, Riveros N. Differential gene expression in skeletal muscle cells after membrane depolarization. J Cell Physiol 2007; 210: 819-830
- 27 Keller C, Hellsten Y, Steensberg A, Pedersen BK. Differential regulation of IL-6 and TNF-alpha via calcineurin in human skeletal muscle cells. Cytokine 2006; 36: 141-147
- 28 Kelly M, Gauthier MS, Saha AK, Ruderman NB. Activation of AMP-activated protein kinase by interleukin-6 in rat skeletal muscle: association with changes in cAMP, energy state, and endogenous fuel mobilization. Diabetes 2009; 58: 1953-1960
- 29 Konhilas JP, Widegren U, Allen DL, Paul AC, Cleary A, Leinwand LA. Loaded wheel running and muscle adaptation in the mouse. Am J Physiol 2005; 289: H455-H465
- 30 Landisch RM, Kosir AM, Nelson SA, Baltgalvis KA, Lowe DA. Adaptive and nonadaptive responses to voluntary wheel running by mdx mice. Muscle Nerve 2008; 38: 1290-1303
- 31 Lazarowski ER, Shea DA, Boucher RC, Harden TK. Release of cellular UDP-glucose as a potential extracellular signaling molecule. Mol Pharmacol 2003; 63: 1190-1197
- 32 Lesniewski LA, Durrant JR, Connell ML, Henson GD, Black AD, Donato AJ, Seals DR. Aerobic exercise reverses arterial inflammation with aging in mice. Am J Physiol 2011; 301: H1025-H1032
- 33 Liu YF, Chen HI, Wu CL, Kuo YM, Yu L, Huang AM, Wu FS, Chuang JI, Jen CJ. Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I. J Physiol 2009; 587: 3221-3231
- 34 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408
- 35 Meek TH, Lonquich BP, Hannon RM, Garland Jr T. Endurance capacity of mice selectively bred for high voluntary wheel running. J Exp Biol 2009; 212: 2908-2917
- 36 Mortensen SP, Gonzalez-Alonso J, Nielsen JJ, Saltin B, Hellsten Y. Muscle interstitial ATP and norepinephrine concentrations in the human leg during exercise and ATP infusion. J Appl Physiol 2009; 107: 1757-1762
- 37 Osorio-Fuentealba C, Contreras-Ferrat AE, Altamirano F, Espinosa A, Li Q, Niu W, Lavandero S, Klip A, Jaimovich E. Electrical stimuli release ATP to increase gLUT4 translocation and glucose uptake via PI3Kgamma-Akt-AS160 in skeletal muscle cells. Diabetes 2012;
- 38 Pedersen BK. The diseasome of physical inactivity – and the role of myokines in muscle – fat cross talk. J Physiol 2009; 587: 5559-5568
- 39 Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008; 88: 1379-1406
- 40 Philp A, Chen A, Lan D, Meyer GA, Murphy AN, Knapp AE, Olfert IM, McCurdy CE, Marcotte GR, Hogan MC, Baar K, Schenk S. Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise. J Biol Chem 2011; 286: 30561-30570
- 41 Powell JA, Carrasco MA, Adams DS, Drouet B, Rios J, Muller M, Estrada M, Jaimovich E. IP(3) receptor function and localization in myotubes: an unexplored Ca(2+) signaling pathway in skeletal muscle. J Cell Sci 2001; 114: 3673-3683
- 42 Rezende EL, Garland Jr T, Chappell MA, Malisch JL, Gomes FR. Maximum aerobic performance in lines of Mus selected for high wheel-running activity: effects of selection, oxygen availability and the mini-muscle phenotype. J Exp Biol 2006; 209: 115-127
- 43 Rockl KS, Hirshman MF, Brandauer J, Fujii N, Witters LA, Goodyear LJ. Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. Diabetes 2007; 56: 2062-2069
- 44 Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011; 1813: 878-888
- 45 Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J 2003; 17: 884-886
- 46 Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol 2003; 285: E433-E437
- 47 Swallow JG, Garland Jr T, Carter PA, Zhan WZ, Sieck GC. Effects of voluntary activity and genetic selection on aerobic capacity in house mice (Mus domesticus). J Appl Physiol 1998; 84: 69-76
- 48 van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, Pedersen BK. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 2003; 88: 3005-3010
- 49 Waters RP, Renner KJ, Pringle RB, Summers CH, Britton SL, Koch LG, Swallow JG. Selection for aerobic capacity affects corticosterone, monoamines and wheel-running activity. Physiol Behav 2008; 93: 1044-1054
- 50 Wolsk E, Mygind H, Grondahl TS, Pedersen BK, van Hall G. IL-6 selectively stimulates fat metabolism in human skeletal muscle. Am J Physiol 2010; 299: E832-E840