Int J Sports Med 2019; 40(01): 16-22
DOI: 10.1055/a-0781-2527
Physiology & Biochemistry
© Georg Thieme Verlag KG Stuttgart · New York

Antioxidants Facilitate High–intensity Exercise IL–15 Expression in Skeletal Muscle

Alberto Pérez-López
1   Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, Acalá de Henares, Spain
2   Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria - Campus de Tafira, Las Palmas de Gran Canaria, Spain
,
Marcos Martin-Rincon
2   Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria - Campus de Tafira, Las Palmas de Gran Canaria, Spain
3   Department of Physical Education, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
,
Alfredo Santana
2   Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria - Campus de Tafira, Las Palmas de Gran Canaria, Spain
4   Complejo Hospitalario Universitario Insular-Materno Infantil de Las Palmas de Gran Canaria, Clinical Genetics Unit, Las Palmas de Gran Canaria, Spain
,
Ismael Perez-Suarez
2   Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria - Campus de Tafira, Las Palmas de Gran Canaria, Spain
3   Department of Physical Education, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
,
Cecilia Dorado
2   Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria - Campus de Tafira, Las Palmas de Gran Canaria, Spain
3   Department of Physical Education, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
,
Jose A. L. Calbet
2   Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria - Campus de Tafira, Las Palmas de Gran Canaria, Spain
3   Department of Physical Education, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
,
David Morales-Alamo
2   Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria - Campus de Tafira, Las Palmas de Gran Canaria, Spain
3   Department of Physical Education, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
› Institutsangaben
Weitere Informationen

Publikationsverlauf



accepted 19. Oktober 2018

Publikationsdatum:
29. November 2018 (online)

Abstract

Interleukin (IL)-15 stimulates mitochondrial biogenesis, fat oxidation, glucose uptake and myogenesis in skeletal muscle. However, the mechanisms by which exercise triggers IL-15 expression remain to be elucidated in humans. This study aimed at determining whether high-intensity exercise and exercise-induced RONS stimulate IL-15/IL-15Rα expression and its signaling pathway (STAT3) in human skeletal muscle. Nine volunteers performed a 30-s Wingate test in normoxia and hypoxia (PIO2=75 mmHg), 2 h after placebo or antioxidant administration (α-lipoic acid, vitamin C and E) in a randomized double-blind design. Blood samples and muscle biopsies (vastus lateralis) were obtained before, immediately after, and 30 and 120 min post-exercise. Sprint exercise upregulated skeletal muscle IL-15 protein expression (ANOVA, P=0.05), an effect accentuated by antioxidant administration in hypoxia (ANOVA, P=0.022). In antioxidant conditions, the increased IL-15 expression at 120 min post-exercise (33%; P=0.017) was associated with the oxygen deficit caused by the sprint (r=–0.54; P=0.020); while, IL-15 and Tyr705-STAT3 AUCs were also related (r=0.50; P=0.036). Antioxidant administration promotes IL-15 protein expression in human skeletal muscle after sprint exercise, particularly in severe acute hypoxia. Therefore, during intense muscle contraction, a reduced PO2 and glycolytic rate, and possibly, an attenuated RONS generation may facilitate IL-15 production, accompanied by STAT3 activation, in a process that does not require AMPK phosphorylation.

 
  • References

  • 1 Busquets S, Figueras M, Almendro V, Lopez-Soriano FJ, Argiles JM. Interleukin-15 increases glucose uptake in skeletal muscle. An antidiabetogenic effect of the cytokine. Biochim Biophys Acta 2006; 1760: 1613-1617
  • 2 Calbet JA, Losa-Reyna J, Torres-Peralta R, Rasmussen P, Ponce-Gonzalez JG, Sheel AW, de la Calle-Herrero J, Guadalupe-Grau A, Morales-Alamo D, Fuentes T, Rodriguez-Garcia L, Siebenmann C, Boushel R, Lundby C. Limitations to oxygen transport and utilization during sprint exercise in humans: evidence for a functional reserve in muscle O2 diffusing capacity. J Physiol 2015; 593: 4649-4664
  • 3 Crane JD, MacNeil LG, Lally JS, Ford RJ, Bujak AL, Brar IK, Kemp BE, Raha S, Steinberg GR, Tarnopolsky MA. Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging. Aging Cell 2015; 14: 625-634
  • 4 Deshmukh AS, Hawley JA, Zierath JR. Exercise-induced phospho-proteins in skeletal muscle. Int J Obes (Lond) 2008; 32 (Suppl. 04) S18-S23
  • 5 Gorostiaga EM, Navarro-Amezqueta I, Calbet JA, Hellsten Y, Cusso R, Guerrero M, Granados C, Gonzalez-Izal M, Ibanez J, Izquierdo M. Energy metabolism during repeated sets of leg press exercise leading to failure or not. PLoS One 2012; 7: e40621
  • 6 Guerra B, Gomez-Cabrera MC, Ponce-Gonzalez JG, Martinez-Bello VE, Guadalupe-Grau A, Santana A, Sebastia V, Vina J, Calbet JA. Repeated muscle biopsies through a single skin incision do not elicit muscle signaling, but IL-6 mRNA and STAT3 phosphorylation increase in injured muscle. J Appl Physiol (1985) 2011; 110: 1708-1715
  • 7 Guerra B, Guadalupe-Grau A, Fuentes T, Ponce-Gonzalez JG, Morales-Alamo D, Olmedillas H, Guillen-Salgado J, Santana A, Calbet JA. SIRT1, AMP-activated protein kinase phosphorylation and downstream kinases in response to a single bout of sprint exercise: Influence of glucose ingestion. Eur J Appl Physiol 2010; 109: 731-743
  • 8 Harriss DJ, Macsween A, Atkinson G. Standards for ethics in sport and exercise science research: 2018 update. Int J Sports Med 2017; 38: 1126-1131
  • 9 Krolopp JE, Thornton SM, Abbott MJ. IL-15 activates the Jak3/STAT3 signaling pathway to mediate glucose uptake in skeletal muscle cells. Front Physiol 2016; 7: 626
  • 10 Lee GA, Lai YG, Chen RJ, Liao NS. Interleukin 15 activates Akt to protect astrocytes from oxygen glucose deprivation-induced cell death. Cytokine 2017; 92: 68-74
  • 11 Li F, Li Y, Tang Y, Lin B, Kong X, Oladele OA, Yin Y. Protective effect of myokine IL-15 against H2O2-mediated oxidative stress in skeletal muscle cells. Mol Biol Rep 2014; 41: 7715-7722
  • 12 Liu J, Jing X, Gan L, Sun C. The JAK2/STAT3 signal pathway regulates the expression of genes related to skeletal muscle development and energy metabolism in mice and mouse skeletal muscle cells. Biosci Biotechnol Biochem 2012; 76: 1866-1870
  • 13 Loro E, Seifert EL, Moffat C, Romero F, Mishra MK, Sun Z, Krajacic P, Anokye-Danso F, Summer RS, Ahima RS, Khurana TS. IL-15Ralpha is a determinant of muscle fuel utilization, and its loss protects against obesity. Am J Physiol Regul Integr Comp Physiol 2015; 309: R835-R844
  • 14 Molanouri Shamsi M, Hassan ZH, Gharakhanlou R, Quinn LS, Azadmanesh K, Baghersad L, Isanejad A, Mahdavi M. Expression of interleukin-15 and inflammatory cytokines in skeletal muscles of STZ-induced diabetic rats: effect of resistance exercise training. Endocrine 2014; 46: 60-69
  • 15 Morales-Alamo D, Calbet JA. Free radicals and sprint exercise in humans. Free Radic Res 2014; 48: 30-42
  • 16 Morales-Alamo D, Calbet JAL. AMPK signaling in skeletal muscle during exercise: Role of reactive oxygen and nitrogen species. Free Radic Biol Med 2016; 98: 68-77
  • 17 Morales-Alamo D, Guerra B, Ponce-Gonzalez JG, Guadalupe-Grau A, Santana A, Martin-Rincon M, Gelabert-Rebato M, Cadefau JA, Cusso R, Dorado C, Calbet JAL. Skeletal muscle signaling, metabolism and performance during sprint exercise in severe acute hypoxia after the ingestion of antioxidants. J Appl Physiol (1985) 2017; 123: 1235-1245
  • 18 Morales-Alamo D, Guerra B, Santana A, Martin-Rincon M, Gelabert-Rebato M, Dorado C, Calbet JAL. Skeletal muscle pyruvate dehydrogenase phosphorylation and lactate accumulation during sprint exercise in normoxia and severe acute hypoxia: Effects of antioxidants. Front Physiol 2018; 9: 188
  • 19 Morales-Alamo D, Ponce-Gonzalez JG, Guadalupe-Grau A, Rodriguez-Garcia L, Santana A, Cusso MR, Guerrero M, Guerra B, Dorado C, Calbet JA. Increased oxidative stress and anaerobic energy release, but blunted Thr172-AMPKalpha phosphorylation, in response to sprint exercise in severe acute hypoxia in humans. J Appl Physiol (1985) 2012; 113: 917-928
  • 20 Morales-Alamo D, Ponce-Gonzalez JG, Guadalupe-Grau A, Rodriguez-Garcia L, Santana A, Cusso R, Guerrero M, Dorado C, Guerra B, Calbet JA. Critical role for free radicals on sprint exercise-induced CaMKII and AMPKalpha phosphorylation in human skeletal muscle. J Appl Physiol (1985) 2013; 114: 566-577
  • 21 Nielsen AR, Mounier R, Plomgaard P, Mortensen OH, Penkowa M, Speerschneider T, Pilegaard H, Pedersen BK. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J Physiol 2007; 584: 305-312
  • 22 O'Leary MF, Wallace GR, Bennett AJ, Tsintzas K, Jones SW. IL-15 promotes human myogenesis and mitigates the detrimental effects of TNFalpha on myotube development. Sci Rep 2017; 7: 12997
  • 23 Pérez-López A, McKendry J, Martin-Rincon M, Morales-Alamo D, Perez-Kohler B, Valades D, Bujan J, Calbet JAL, Breen L. Skeletal muscle IL-15/IL-15Ralpha and myofibrillar protein synthesis after resistance exercise. Scand J Med Sci Sports 2018; 28: 116-125
  • 24 Quinn LS, Anderson BG, Conner JD, Wolden-Hanson T. IL-15 overexpression promotes endurance, oxidative energy metabolism, and muscle PPARdelta, SIRT1, PGC-1alpha, and PGC-1beta expression in male mice. Endocrinology 2013; 154: 232-245
  • 25 Quinn LS, Anderson BG, Conner JD, Wolden-Hanson T, Marcell TJ. IL-15 is required for postexercise induction of the pro-oxidative mediators PPARdelta and SIRT1 in male mice. Endocrinology 2014; 155: 143-155
  • 26 Richardson RS, Donato AJ, Uberoi A, Wray DW, Lawrenson L, Nishiyama S, Bailey DM. Exercise-induced brachial artery vasodilation: Role of free radicals. Am J Physiol Heart Circ Physiol 2007; 292: H1516-H1522
  • 27 Rinnov A, Yfanti C, Nielsen S, Akerstrom TC, Peijs L, Zankari A, Fischer CP, Pedersen BK. Endurance training enhances skeletal muscle interleukin-15 in human male subjects. Endocrine 2014; 45: 271-278
  • 28 Romagnoli M, Gomez-Cabrera MC, Perrelli MG, Biasi F, Pallardo FV, Sastre J, Poli G, Vina J. Xanthine oxidase-induced oxidative stress causes activation of NF-kappaB and inflammation in the liver of type I diabetic rats. Free Radic Biol Med 2010; 49: 171-177
  • 29 Sun H, Liu D. Hydrodynamic delivery of interleukin 15 gene promotes resistance to high fat diet-induced obesity, fatty liver and improves glucose homeostasis. Gene Ther 2015; 22: 341-347
  • 30 Thornton SM, Krolopp JE, Abbott MJ. IL-15 mediates mitochondrial activity through a PPARdelta-dependent-PPARalpha-independent mechanism in skeletal muscle cells. PPAR Res 2016; 2016: 5465804
  • 31 Weigert C, Hennige AM, Lehmann R, Brodbeck K, Baumgartner F, Schauble M, Haring HU, Schleicher ED. Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells. J Biol Chem 2006; 281: 7060-7067
  • 32 Wolsk E, Mygind H, Grondahl TS, Pedersen BK, van Hall G. The role of leptin in human lipid and glucose metabolism: the effects of acute recombinant human leptin infusion in young healthy males. Am J Clin Nutr 2011; 94: 1533-1544