Comprehensive Physiology Wiley Online Library

Reactive Oxygen Species: Impact on Skeletal Muscle

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Abstract

It is well established that contracting muscles produce both reactive oxygen and nitrogen species. Although the sources of oxidant production during exercise continue to be debated, growing evidence suggests that mitochondria are not the dominant source. Regardless of the sources of oxidants in contracting muscles, intense and prolonged exercise can result in oxidative damage to both proteins and lipids in the contracting myocytes. Further, oxidants regulate numerous cell signaling pathways and modulate the expression of many genes. This oxidant‐mediated change in gene expression involves changes at transcriptional, mRNA stability, and signal transduction levels. Furthermore, numerous products associated with oxidant‐modulated genes have been identified and include antioxidant enzymes, stress proteins, and mitochondrial electron transport proteins. Interestingly, low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species result in contractile dysfunction and fatigue. Ongoing research continues to explore the redox‐sensitive targets in muscle that are responsible for both redox regulation of muscle adaptation and oxidant‐mediated muscle fatigue. © 2011 American Physiological Society. Compr Physiol 1:941‐969, 2011.

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Figure 1. Figure 1.

Locations of the principal enzymatic and nonenzymatic antioxidants found in cells. Abbreviations: GPX: glutathione peroxidase; SOD1: superoxide dismutase 1; SOD2: superoxide dismutase 2.

Figure 2. Figure 2.

Four broad classes of biomarkers are commonly used to assess the presence of oxidative stress in cells or tissues. These categories include the measurement of oxidants, cellular levels of antioxidants, oxidation products, and the antioxidant/pro‐oxidant balance. Abbreviations: 8‐OH‐dG: 8‐hydroxydeoxyguanosine; GSH/GSSG: ratio of reduced glutathione to oxidized glutathione.

Figure 3. Figure 3.

Potential sites for the production of superoxide and nitric oxide (NO) in skeletal muscle. Abbreviations: CAT: catalase; SOD1: superoxide dismutase 1; SOD2: superoxide dismutase 2; GPX: glutathione peroxidase.

Figure 4. Figure 4.

A theoretical model proposed by Reid and colleagues that describes the biphasic effect of ROS on skeletal muscle force production. Point 1 represents the force production by unfatigued muscle exposed to antioxidants or a reducing agent. Point 2 illustrates the force generated by muscle in its basal state (i.e., no antioxidants or oxidants added). Point 3 illustrates the force produced by unfatigued skeletal muscle exposed to low levels of oxidants; this represents the optimal redox state for force production. Point 4 illustrates the deleterious effects of excessive ROS on skeletal muscle force. Figure is redrawn from work by Reid .

Figure 5. Figure 5.

Diagram of reputed redox sensitive targets in skeletal muscle that can impact muscle force production. Redrawn from Smith and Reid . Abbreviations: SOD: superoxide dismutase; NOS: nitric oxide synthase; NO: nitric oxide; SERCA: sarcoplasmic reticulum calcium ATPase.

Figure 6. Figure 6.

Hypothetical illustration of function and expression of antioxidants in the skeletal muscle. Abbreviations: ROS: reactive oxygen species, NO: nitric oxide; CREB: cAMP‐response element binding protein; NRF‐1: nuclear respiratory factor‐1; SOD2: superoxide dismutase 2; UCP3: uncoupling protein 3; JNK: c‐Jun amino‐terminal kinase; MAPK: mitogen‐activated protein kinase; NFκB: nuclear factor κB; inducible nitric oxide synthase (iNOS), IL: interlurekin.



Figure 1.

Locations of the principal enzymatic and nonenzymatic antioxidants found in cells. Abbreviations: GPX: glutathione peroxidase; SOD1: superoxide dismutase 1; SOD2: superoxide dismutase 2.



Figure 2.

Four broad classes of biomarkers are commonly used to assess the presence of oxidative stress in cells or tissues. These categories include the measurement of oxidants, cellular levels of antioxidants, oxidation products, and the antioxidant/pro‐oxidant balance. Abbreviations: 8‐OH‐dG: 8‐hydroxydeoxyguanosine; GSH/GSSG: ratio of reduced glutathione to oxidized glutathione.



Figure 3.

Potential sites for the production of superoxide and nitric oxide (NO) in skeletal muscle. Abbreviations: CAT: catalase; SOD1: superoxide dismutase 1; SOD2: superoxide dismutase 2; GPX: glutathione peroxidase.



Figure 4.

A theoretical model proposed by Reid and colleagues that describes the biphasic effect of ROS on skeletal muscle force production. Point 1 represents the force production by unfatigued muscle exposed to antioxidants or a reducing agent. Point 2 illustrates the force generated by muscle in its basal state (i.e., no antioxidants or oxidants added). Point 3 illustrates the force produced by unfatigued skeletal muscle exposed to low levels of oxidants; this represents the optimal redox state for force production. Point 4 illustrates the deleterious effects of excessive ROS on skeletal muscle force. Figure is redrawn from work by Reid .



Figure 5.

Diagram of reputed redox sensitive targets in skeletal muscle that can impact muscle force production. Redrawn from Smith and Reid . Abbreviations: SOD: superoxide dismutase; NOS: nitric oxide synthase; NO: nitric oxide; SERCA: sarcoplasmic reticulum calcium ATPase.



Figure 6.

Hypothetical illustration of function and expression of antioxidants in the skeletal muscle. Abbreviations: ROS: reactive oxygen species, NO: nitric oxide; CREB: cAMP‐response element binding protein; NRF‐1: nuclear respiratory factor‐1; SOD2: superoxide dismutase 2; UCP3: uncoupling protein 3; JNK: c‐Jun amino‐terminal kinase; MAPK: mitogen‐activated protein kinase; NFκB: nuclear factor κB; inducible nitric oxide synthase (iNOS), IL: interlurekin.

References
 1. Abraham RZ, Kobzik L, Moody MR, Reid MB, Stamler JS. Cyclic GMP is a second messenger by which nitric oxide inhibits diaphragm contraction. Comp Biochem Physiol A Mol Integr Physiol 119: 177–183, 1998.
 2. Abramson JJ, Salama G. Critical sulfhydryls regulate calcium release from sarcoplasmic reticulum. J Bioenerg Biomembr 21: 283–294, 1989.
 3. Abramson JJ, Zable AC, Favero TG, Salama G. Thimerosal interacts with the Ca2+ release channel ryanodine receptor from skeletal muscle sarcoplasmic reticulum. J Biol Chem 270: 29644–29647, 1995.
 4. Adams V, Nehrhoff B, Spate U, Linke A, Schulze PC, Baur A, Gielen S, Hambrecht R, Schuler G. Induction of iNOS expression in skeletal muscle by IL‐1beta and NFkappaB activation: An in vitro and in vivo study. Cardiovasc Res 54: 95–104, 2002.
 5. Adams V, Spate U, Krankel N, Schulze PC, Linke A, Schuler G, Hambrecht R. Nuclear factor‐kappa B activation in skeletal muscle of patients with chronic heart failure: Correlation with the expression of inducible nitric oxide synthase. Eur J Cardiovasc Prev Rehabil 10: 273–277, 2003.
 6. Adhihetty PJ, Ljubicic V, Menzies KJ, Hood DA. Differential susceptibility of subsarcolemmal and intermyofibrillar mitochondria to apoptotic stimuli. Am J Physiol Cell Physiol 289: C994–C1001, 2005.
 7. Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB, Williams RS, Yan Z. Exercise stimulates Pgc‐1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem 280: 19587–19593, 2005.
 8. Albertini M, Lafortuna C, Aguggini G. Effects of nitric oxide on diaphragmatic muscle endurance and strength in pigs. Exp Physiol 82: 99–106, 1997.
 9. Aldred S. Oxidative and nitrative changes seen in lipoproteins following exercise. Atherosclerosis 192: 1–8, 2007.
 10. Alessio HM, Goldfarb AH. Lipid peroxidation and scavenger enzymes during exercise: Adaptive response to training. J Appl Physiol 64: 1333–1336, 1988.
 11. Alessio HM, Goldfarb AH, Cutler RG. MDA content increases in fast‐ and slow‐twitch skeletal muscle with intensity of exercise in a rat. Am J Physiol 255: C874–C877, 1988.
 12. Allen DG, Lamb GD, Westerblad H. Skeletal muscle fatigue: Cellular mechanisms. Physiol Rev 88: 287–332, 2008.
 13. Allen RG, Tresini M. Oxidative stress and gene regulation. Free Radic Biol Med 28: 463–499, 2000.
 14. Ameredes BT, Provenzano MA. Influence of nitric oxide on vascular resistance and muscle mechanics during tetanic contractions in situ. J Appl Physiol 87: 142–151, 1999.
 15. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant‐ and radical‐caused aging and cancer: A hypothesis. Proc Natl Acad Sci U S A 78: 6858–6862, 1981.
 16. Anderson EJ, Neufer PD. Type II skeletal myofibers possess unique properties that potentiate mitochondrial H(2)O(2) generation. Am J Physiol Cell Physiol 290: C844–C851, 2006.
 17. Anderson EJ, Yamazaki H, Neufer PD. Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid‐supported respiration. J Biol Chem 282: 31257–31266, 2007.
 18. Andrade FH, Reid MB, Allen DG, Westerblad H. Effect of hydrogen peroxide and dithiothreitol on contractile function of single skeletal muscle fibres from the mouse. J Physiol 509 (Pt 2): 565–575, 1998a.
 19. Andrade FH, Reid MB, Allen DG, Westerblad H. Effect of nitric oxide on single skeletal muscle fibres from the mouse. J Physiol 509 (Pt 2): 577–586, 1998b.
 20. Andrade FH, Reid MB, Westerblad H. Contractile response of skeletal muscle to low peroxide concentrations: Myofibrillar calcium sensitivity as a likely target for redox‐modulation. Faseb J 15: 309–311, 2001.
 21. Antunes F, Cadenas E. Estimation of H2O2 gradients across biomembranes. FEBS Lett 475: 121–126, 2000.
 22. Anzai K, Ogawa K, Ozawa T, Yamamoto H. Oxidative modification of ion channel activity of ryanodine receptor. Antioxid Redox Signal 2: 35–40, 2000.
 23. Anzueto A, Andrade FH, Maxwell LC, Levine SM, Lawrence RA, Gibbons WJ, Jenkinson SG. Resistive breathing activates the glutathione redox cycle and impairs performance of rat diaphragm. J Appl Physiol 72: 529–534, 1992.
 24. Aoi W, Naito Y, Takanami Y, Kawai Y, Sakuma K, Ichikawa H, Yoshida N, Yoshikawa T. Oxidative stress and delayed‐onset muscle damage after exercise. Free Radic Biol Med 37: 480–487, 2004.
 25. Arend A, Zilmer M, Vihalemm T, Selstam G, Sepp E. Lipoic acid prevents suppression of connective tissue proliferation in the rat liver induced by n‐3 PUFAs. A pilot study. Ann Nutr Metab 44: 217–222, 2000.
 26. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267: 6102–6109, 2000.
 27. Aronson D, Violan MA, Dufresne SD, Zangen D, Fielding RA, Goodyear LJ. Exercise stimulates the mitogen‐activated protein kinase pathway in human skeletal muscle. J Clin Invest 99: 1251–1257, 1997.
 28. Ashton T, Rowlands CC, Jones E, Young IS, Jackson SK, Davies B, Peters JR. Electron spin resonance spectroscopic detection of oxygen‐centred radicals in human serum following exhaustive exercise. Eur J Appl Physiol Occup Physiol 77: 498–502, 1998.
 29. Atalay M, Lappalainen J, Sen CK. Dietary antioxidants for the athlete. Curr Sports Med Rep 5: 182–186, 2006.
 30. Atherton PJ, Higginson JM, Singh J, Wackerhage H. Concentrations of signal transduction proteins exercise and insulin responses in rat extensor digitorum longus and soleus muscles. Mol Cell Biochem 261: 111–116, 2004.
 31. Avery NG, Kaiser JL, Sharman MJ, Scheett TP, Barnes DM, Gomez AL, Kraemer WJ, Volek JS. Effects of vitamin E supplementation on recovery from repeated bouts of resistance exercise. J Strength Cond Res 17: 801–809, 2003.
 32. Azzi A, Davies KJA, Kelly F. Free radical biology—terminology and critical thinking. Febs Lett 558: 3–6, 2004.
 33. Azzi A, Gysin R, Kempna P, Munteanu A, Villacorta L, Visarius T, Zingg JM. Regulation of gene expression by alpha‐tocopherol. Biol Chem 385: 585–591, 2004.
 34. Azzi A, Gysin R, Kempna P, Ricciarelli R, Villacorta L, Visarius T, Zingg JM. The role of alpha‐tocopherol in preventing disease: From epidemiology to molecular events. Mol Aspects Med 24: 325–336, 2003.
 35. Baar K, Esser K. Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am J Physiol 276: C120–C127, 1999.
 36. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, Holloszy JO. Adaptations of skeletal muscle to exercise: Rapid increase in the transcriptional coactivator PGC‐1. FASEB J 16: 1879–1886, 2002.
 37. Baeuerle PA, Baltimore D. Activation of DNA‐binding activity in an apparently cytoplasmic precursor of the NF‐kappa B transcription factor. Cell 53: 211–217, 1988.
 38. Balon TW. Integrative biology of nitric oxide and exercise. Exerc Sport Sci Rev 27: 219–253, 1999.
 39. Balon TW, Nadler JL. Nitric oxide release is present from incubated skeletal muscle preparations. J Appl Physiol 77: 2519–2521, 1994.
 40. Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: A major physiologic cytoprotectant. Proc Natl Acad Sci U S A 99: 16093–16098, 2002.
 41. Barclay JK, Hansel M. Free radicals may contribute to oxidative skeletal muscle fatigue. Can J Physiol Pharmacol 69: 279–284, 1991.
 42. Barclay JK, Reading SA, Murrant CL, Woodley NE. Inotropic effects on mammalian skeletal muscle change with contraction frequency. Can J Physiol Pharmacol 81: 753–758, 2003.
 43. Barja G. Mitochondrial oxygen radical generation and leak: Sites of production in states 4 and 3, organ specificity, and relation to aging and longevity. J Bioenerg Biomembr 31: 347–366, 1999.
 44. Barnes KA, Samson SE, Grover AK. Sarco/endoplasmic reticulum Ca2+‐pump isoform SERCA3a is more resistant to superoxide damage than SERCA2b. Mol Cell Biochem 203: 17–21, 2000.
 45. Belia S, Pietrangelo T, Fulle S, Menchetti G, Cecchini E, Felaco M, Vecchiet J, Fano G. Sodium nitroprusside, a NO donor, modifies Ca2+ transport and mechanical properties in frog skeletal muscle. J Muscle Res Cell Motil 19: 865–876, 1998.
 46. Bergelson S, Pinkus R, Daniel V. Induction of AP‐1 (Fos/Jun) by chemical agents mediates activation of glutathione S‐transferase and quinone reductase gene expression. Oncogene 9: 565–571, 1994.
 47. Berndt C, Lillig CH, Holmgren A. Thiol‐based mechanisms of the thioredoxin and glutaredoxin systems: Implications for diseases in the cardiovascular system. Am J Physiol Heart Circ Physiol 292: H1227–H1236, 2007.
 48. Bjornstedt M, Kumar S, Bjorkhem L, Spyrou G, Holmgren A. Selenium and the thioredoxin and glutaredoxin systems. Biomed Environ Sci 10: 271–279, 1997.
 49. Bjornstedt M, Xue J, Huang W, Akesson B, Holmgren A. The thioredoxin and glutaredoxin systems are efficient electron donors to human plasma glutathione peroxidase. J Biol Chem 269: 29382–29384, 1994.
 50. Block F, Schwarz M. Effects of antioxidants on ischemic retinal dysfunction. Exp Eye Res 64: 559–564, 1997.
 51. Bolanos JP, Peuchen S, Heales SJ, Land JM, Clark JB. Nitric oxide‐mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes. J Neurochem 63: 910–916, 1994.
 52. Boluyt MO, Loyd AM, Roth MH, Randall MJ, Song EY. Activation of JNK in rat heart by exercise: Effect of training. Am J Physiol Heart Circ Physiol 285: H2639–H2647, 2003.
 53. Boveris A, Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134: 707–716, 1973.
 54. Bowles DK, Torgan CE, Ebner S, Kehrer JP, Ivy JL, Starnes JW. Effects of acute, submaximal exercise on skeletal muscle vitamin E. Free Radic Res Commun 14: 139–143, 1991.
 55. Bowman WC, Lam FY, Rodger IW, Shahid M. Cyclic nucleotides and contractility of isolated soleus muscle. Br J Pharmacol 84: 259–264, 1985.
 56. Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, Pakay JL, Parker N. Mitochondrial superoxide: Production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med 37: 755–767, 2004.
 57. Brand MD, Esteves TC. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2: 85–93, 2005.
 58. Brigelius‐Flohe R. Tissue‐specific functions of individual glutathione peroxidases. Free radical biology & medicine 27: 951–965, 1999.
 59. Brigelius‐Flohe R. Glutathione peroxidases and redox‐regulated transcription factors. Biol Chem 387: 1329–1335, 2006.
 60. Brown GC. Nitric oxide regulates mitochondrial respiration and cell functions by inhibiting cytochrome oxidase. FEBS Lett 369: 136–139, 1995.
 61. Brunori M, Giuffre A, Forte E, Mastronicola D, Barone MC, Sarti P. Control of cytochrome c oxidase activity by nitric oxide. Biochim Biophys Acta 1655: 365–371, 2004.
 62. Bruton JD, Place N, Yamada T, Silva JP, Andrade FH, Dahlstedt AJ, Zhang SJ, Katz A, Larsson NG, Westerblad H. Reactive oxygen species and fatigue‐induced prolonged low‐frequency force depression in skeletal muscle fibres of rats, mice and SOD2 overexpressing mice. J Physiol 586: 175–184, 2008.
 63. Bryant RJ, Ryder J, Martino P, Kim J, Craig BW. Effects of vitamin E and C supplementation either alone or in combination on exercise‐induced lipid peroxidation in trained cyclists. J Strength Cond Res 17: 792–800, 2003.
 64. Burke M, Reisler F, Harrington WF. Effect of bridging the two essential thiols of myosin on its spectral and actin‐binding properties. Biochemistry 15: 1923–1927, 1976.
 65. Callahan LA, Nethery D, Stofan D, DiMarco A, Supinski G. Free radical‐induced contractile protein dysfunction in endotoxin‐induced sepsis. Am J Respir Cell Mol Biol 24: 210–217, 2001.
 66. Cao X, Phillis JW. The free radical scavenger, alpha‐lipoic acid, protects against cerebral ischemia‐reperfusion injury in gerbils. Free Radic Res 23: 365–370, 1995.
 67. Carr A, Frei B. Does vitamin C act as a pro‐oxidant under physiological conditions? Faseb J 13: 1007–1024, 1999.
 68. Carroll MP, May WS. Protein kinase C‐mediated serine phosphorylation directly activates Raf‐1 in murine hematopoietic cells. J Biol Chem 269: 1249–1256, 1994.
 69. Catani MV, Savini I, Duranti G, Caporossi D, Ceci R, Sabatini S, Avigliano L. Nuclear factor kappaB and activating protein 1 are involved in differentiation‐related resistance to oxidative stress in skeletal muscle cells. Free Radic Biol Med 37: 1024–1036, 2004.
 70. Chan JY, Kwong M. Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic‐leucine zipper protein. Biochim Biophys Acta 1517: 19–26, 2000.
 71. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev 59: 527–605, 1979.
 72. Chelikani P, Fita I, Loewen PC. Diversity of structures and properties among catalases. Cell Mol Life Sci 61: 192–208, 2004.
 73. Chen LE, Seaber AV, Nasser RM, Stamler JS, Urbaniak JR. Effects of S‐nitroso‐N‐acetylcysteine on contractile function of reperfused skeletal muscle. Am J Physiol 274: R822–R829, 1998.
 74. Cherednichenko G, Zima AV, Feng W, Schaefer S, Blatter LA, Pessah IN. NADH oxidase activity of rat cardiac sarcoplasmic reticulum regulates calcium‐induced calcium release. Circ Res 94: 478–486, 2004.
 75. Clanton TL, Zuo L, Klawitter P. Oxidants and skeletal muscle function: Physiologic and pathophysiologic implications. Proc Soc Exp Biol Med 222: 253–262, 1999.
 76. Clarkson PM. Antioxidants and physical performance. Crit Rev Food Sci Nutr 35: 131–141, 1995.
 77. Clerch LB, Wright A, Chung DJ. Evidence that glutathione peroxidase RNA and manganese superoxide dismutase RNA bind the same protein. Biochem Biophys Res Commun 222: 590–594, 1996.
 78. Coffey VG, Zhong Z, Shield A, Canny BJ, Chibalin AV, Zierath JR, Hawley JA. Early signaling responses to divergent exercise stimuli in skeletal muscle from well‐trained humans. FASEB J 20: 190–192, 2006.
 79. Coirault C, Guellich A, Barbry T, Samuel JL, Riou B, Lecarpentier Y. Oxidative stress of myosin contributes to skeletal muscle dysfunction in rats with chronic heart failure. Am J Physiol Heart Circ Physiol 292: H1009–H1017, 2007.
 80. Commoner B, Townsend J, Pake GE. Free radicals in biological materials. Nature 174: 689–691, 1954.
 81. Coombes JS, Powers SK, Hamilton KL, Demirel HA, Shanely RA, Zergeroglu MA, Sen CK, Packer L, Ji LL. Improved cardiac performance after ischemia in aged rats supplemented with vitamin E and alpha‐lipoic acid. Am J Physiol Regul Integr Comp Physiol 279: R2149–R2155, 2000.
 82. Coombes JS, Powers SK, Rowell B, Hamilton KL, Dodd SL, Shanely RA, Sen CK, Packer L. Effects of vitamin E and alpha‐lipoic acid on skeletal muscle contractile properties. J Appl Physiol 90: 1424–1430, 2001.
 83. Coombes JS, Rowell B, Dodd SL, Demirel HA, Naito H, Shanely RA, Powers SK. Effects of vitamin E deficiency on fatigue and muscle contractile properties. Eur J Appl Physiol 87: 272–277, 2002.
 84. Cooper CE, Vollaard NB, Choueiri T, Wilson MT. Exercise, free radicals and oxidative stress. Biochem Soc Trans 30: 280–285, 2002.
 85. Cortright RN, Zheng D, Jones JP, Fluckey JD, DiCarlo SE, Grujic D, Lowell BB, Dohm GL. Regulation of skeletal muscle UCP‐2 and UCP‐3 gene expression by exercise and denervation. Am J Physiol 276: E217–E221, 1999.
 86. Cowan DB, Weisel RD, Williams WG, Mickle DA. The regulation of glutathione peroxidase gene expression by oxygen tension in cultured human cardiomyocytes. J Mol Cell Cardiol 24: 423–433, 1992.
 87. Cowan DB, Weisel RD, Williams WG, Mickle DA. Identification of oxygen responsive elements in the 5′‐flanking region of the human glutathione peroxidase gene. J Biol Chem 268: 26904–26910, 1993.
 88. Criswell D, Powers S, Dodd S, Lawler J, Edwards W, Renshler K, Grinton S. High intensity training‐induced changes in skeletal muscle antioxidant enzyme activity. Med Sci Sports Exerc 25: 1135–1140, 1993.
 89. Crowder MS, Cooke R. The effect of myosin sulphydryl modification on the mechanics of fibre contraction. J Muscle Res Cell Motil 5: 131–146, 1984.
 90. Culotta VC, Yang M, O'Halloran TV. Activation of superoxide dismutases: Putting the metal to the pedal. Biochim Biophys Acta 1763: 747–758, 2006.
 91. Daiho T, Kanazawa T. Reduction of disulfide bonds in sarcoplasmic reticulum Ca(2+)‐ATPase by dithiothreitol causes inhibition of phosphoenzyme isomerization in catalytic cycle. This reduction requires binding of both purine nucleotide and Ca2+ to enzyme. J Biol Chem 269: 11060–11064, 1994.
 92. Daneryd P, Aberg F, Dallner G, Ernster L, Schersten T, Soussi B. Coenzymes Q9 and Q10 in skeletal and cardiac muscle in tumour‐bearing exercising rats. Eur J Cancer 31A: 760–765, 1995.
 93. Das KC, Lewis‐Molock Y, White CW. Thiol modulation of TNF alpha and IL‐1 induced MnSOD gene expression and activation of NF‐kappa B. Mol Cell Biochem 148: 45–57, 1995.
 94. Davies KJ, Maguire JJ, Brooks GA, Dallman PR, Packer L. Muscle mitochondrial bioenergetics, oxygen supply, and work capacity during dietary iron deficiency and repletion. Am J Physiol 242: E418–E427, 1982.
 95. Davies KJ, Quintanilha AT, Brooks GA, Packer L. Free radicals and tissue damage produced by exercise. Biochem Biophys Res Commun 107: 1198–1205, 1982.
 96. Davies KJ, Sevanian A, Muakkassah‐Kelly SF, Hochstein P. Uric acid‐iron ion complexes. A new aspect of the antioxidant functions of uric acid. Biochem J 235: 747–754, 1986.
 97. Davies MJ, Fu S, Wang H, Dean RT. Stable markers of oxidant damage to proteins and their application in the study of human disease. Free Radic Biol Med 27: 1151–1163, 1999.
 98. Davis JM, Murphy EA, Carmichael MD, Davis B. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. Am J Physiol Regul Integr Comp Physiol 296: R1071–R1077, 2009.
 99. de Grey AD. A hypothesis for the minimal overall structure of the mammalian plasma membrane redox system. Protoplasma 221: 3–9, 2003.
 100. De la Fuente M, Hernanz A, Vallejo MC. The immune system in the oxidative stress conditions of aging and hypertension: Favorable effects of antioxidants and physical exercise. Antioxid Redox Signal 7: 1356–1366, 2005.
 101. Dekhuijzen PN. Antioxidant properties of N‐acetylcysteine: Their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J 23: 629–636, 2004.
 102. Dekkers JC, van Doornen LJ, Kemper HC. The role of antioxidant vitamins and enzymes in the prevention of exercise‐induced muscle damage. Sports Med 21: 213–238, 1996.
 103. Di Meo S, Venditti P. Mitochondria in exercise‐induced oxidative stress. Biol Signals Recept 10: 125–140, 2001.
 104. Diaz PT, Brownstein E, Clanton TL. Effects of N‐acetylcysteine on in vitro diaphragm function are temperature dependent. J Appl Physiol 77: 2434–2439, 1994.
 105. Diaz PT, Costanza MJ, Wright VP, Julian MW, Diaz JA, Clanton TL. Dithiothreitol improves recovery from in vitro diaphragm fatigue. Med Sci Sports Exerc 30: 421–426, 1998.
 106. Dickinson DA, Forman HJ. Glutathione in defense and signaling: Lessons from a small thiol. Ann N Y Acad Sci 973: 488–504, 2002.
 107. Dillard CJ, Litov RE, Savin WM, Dumelin EE, Tappel AL. Effects of exercise, vitamin E, and ozone on pulmonary function and lipid peroxidation. J Appl Physiol 45: 927–932, 1978.
 108. Diplock AT. Introduction: Markers of oxidative damage and antioxidant modulation. Free Radic Res 33 Suppl: S21–S26, 2000.
 109. Drevet JR. The antioxidant glutathione peroxidase family and spermatozoa: A complex story. Mol Cell Endocrinol 250: 70–79, 2006.
 110. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 82: 47–95, 2002.
 111. Duntas LH. Oxidants, antioxidants in physical exercise and relation to thyroid function. Horm Metab Res 37: 572–576, 2005.
 112. Durham WJ, Arbogast S, Gerken E, Li YP, Reid MB. Progressive nuclear factor‐kappaB activation resistant to inhibition by contraction and curcumin in mdx mice. Muscle Nerve 34: 298–303, 2006.
 113. Durham WJ, Li YP, Gerken E, Farid M, Arbogast S, Wolfe RR, Reid MB. Fatiguing exercise reduces DNA binding activity of NF‐kappaB in skeletal muscle nuclei. J Appl Physiol 97: 1740–1745, 2004.
 114. Duthie GG, Robertson JD, Maughan RJ, Morrice PC. Blood antioxidant status and erythrocyte lipid peroxidation following distance running. Arch Biochem Biophys 282: 78–83, 1990.
 115. El‐Agamey A, Lowe GM, McGarvey DJ, Mortensen A, Phillip DM, Truscott TG, Young AJ. Carotenoid radical chemistry and antioxidant/pro‐oxidant properties. Arch Biochem Biophys 430: 37–48, 2004.
 116. Espinosa A, Leiva A, Pena M, Muller M, Debandi A, Hidalgo C, Carrasco MA, Jaimovich E. Myotube depolarization generates reactive oxygen species through NAD(P)H oxidase; ROS‐elicited Ca2+ stimulates ERK, CREB, early genes. J Cell Physiol 209: 379–388, 2006.
 117. Fabisiak JP, Ritov VB, Kagan VE. Reversible thiol‐dependent activation of ryanodine‐sensitive Ca2+ release channel by etoposide (VP‐16) phenoxyl radical. Antioxid Redox Signal 2: 73–82, 2000.
 118. Fallon KE, Sivyer G, Sivyer K, Dare A. The biochemistry of runners in a 1600 km ultramarathon. Br J Sports Med 33: 264–269, 1999.
 119. Fenster CP, Weinsier RL, Darley‐Usmar VM, Patel RP. Obesity, aerobic exercise, and vascular disease: The role of oxidant stress. Obes Res 10: 964–968, 2002.
 120. Ferreira LF, Gilliam LA, Reid MB. L‐2‐Oxothiazolidine‐4‐carboxylate reverses glutathione oxidation and delays fatigue of skeletal muscle in vitro. J Appl Physiol 107: 211–216, 2009.
 121. Flohe L, Brigelius‐Flohe R, Saliou C, Traber MG, Packer L. Redox regulation of NF‐kappa B activation. Free Radic Biol Med 22: 1115–1126, 1997.
 122. Flohe L, Budde H, Hofmann B. Peroxiredoxins in antioxidant defense and redox regulation. Biofactors 19: 3–10, 2003.
 123. Franco AA, Odom RS, Rando TA. Regulation of antioxidant enzyme gene expression in response to oxidative stress and during differentiation of mouse skeletal muscle. Free Radic Biol Med 27: 1122–1132, 1999.
 124. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem 64: 97–112, 1995.
 125. Fuchs J. Oxidative Injury in Dermatology. NY: Springer‐Verlag, 1992.
 126. Fuchs J, Milbradt R. Antioxidant inhibition of skin inflammation induced by reactive oxidants: Evaluation of the redox couple dihydrolipoate/lipoate. Skin Pharmacol 7: 278–284, 1994.
 127. Fujii Y, Takahashi S, Toyooka H. Protection from diaphragmatic fatigue by nitric oxide synthase inhibitor in dogs. Anaesth Intensive Care 27: 45–48, 1999.
 128. Gaeini AA, Rahnama N, Hamedinia MR. Effects of vitamin E supplementation on oxidative stress at rest and after exercise to exhaustion in athletic students. J Sports Med Phys Fitness 46: 458–461, 2006.
 129. Gandevia SC. Spinal and supraspinal factors in human muscle fatigue. Physiol Rev 81: 1725–1789, 2001.
 130. Ghosh S, Karin M. Missing pieces in the NF‐kappaB puzzle. Cell 109 Suppl: S81–S96, 2002.
 131. Ghosh S, May MJ, Kopp EB. NF‐kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16: 225–260, 1998.
 132. Gladyshev VN, Liu A, Novoselov SV, Krysan K, Sun QA, Kryukov VM, Kryukov GV, Lou MF. Identification and characterization of a new mammalian glutaredoxin (thioltransferase), Grx2. J Biol Chem 276: 30374–30380, 2001.
 133. Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. Uric acid and oxidative stress. Curr Pharm Des 11: 4145–4151, 2005.
 134. Goglia F, Skulachev VP. A function for novel uncoupling proteins: Antioxidant defense of mitochondrial matrix by translocating fatty acid peroxides from the inner to the outer membrane leaflet. FASEB J 17: 1585–1591, 2003.
 135. Gohil K, Rothfuss L, Lang J, Packer L. Effect of exercise training on tissue vitamin E and ubiquinone content. J Appl Physiol 63: 1638–1641, 1987.
 136. Gomez‐Cabrera MC, Borras C, Pallardo FV, Sastre J, Ji LL, Vina J. Decreasing xanthine oxidase‐mediated oxidative stress prevents useful cellular adaptations to exercise in rats. J Physiol 567: 113–120, 2005.
 137. Gomez‐Cabrera MC, Close GL, Kayani A, McArdle A, Vina J, Jackson MJ. Effect of xanthine oxidase‐generated extracellular superoxide on skeletal muscle force generation. Am J Physiol Regul Integr Comp Physiol 298: R2–R8, 2010.
 138. Gomez‐Cabrera MC, Pallardo FV, Sastre J, Vina J, Garcia‐del‐Moral L. Allopurinol and markers of muscle damage among participants in the Tour de France. JAMA 289: 2503–2504, 2003.
 139. Gong MC, Arbogast S, Guo Z, Mathenia J, Su W, Reid MB. Calcium‐independent phospholipase A2 modulates cytosolic oxidant activity and contractile function in murine skeletal muscle cells. J Appl Physiol 100: 399–405, 2006.
 140. Goodyear LJ, Chang PY, Sherwood DJ, Dufresne SD, Moller DE. Effects of exercise and insulin on mitogen‐activated protein kinase signaling pathways in rat skeletal muscle. Am J Physiol 271: E403–E408, 1996.
 141. Gordon JW, Rungi AA, Inagaki H, Hood DA. Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle. J Appl Physiol 90: 389–396, 2001.
 142. Gross WL, Bak MI, Ingwall JS, Arstall MA, Smith TW, Balligand JL, Kelly RA. Nitric oxide inhibits creatine kinase and regulates rat heart contractile reserve. Proc Natl Acad Sci U S A 93: 5604–5609, 1996.
 143. Grune T, Merker K, Sandig G, Davies KJ. Selective degradation of oxidatively modified protein substrates by the proteasome. Biochem Biophys Res Commun 305: 709–718, 2003.
 144. Guo Z, Boekhoudt GH, Boss JM. Role of the intronic enhancer in tumor necrosis factor‐mediated induction of manganous superoxide dismutase. J Biol Chem 278: 23570–23578, 2003.
 145. Gutierrez‐Martin Y, Martin‐Romero FJ, Inesta‐Vaquera FA, Gutierrez‐Merino C, Henao F. Modulation of sarcoplasmic reticulum Ca(2+)‐ATPase by chronic and acute exposure to peroxynitrite. Eur J Biochem 271: 2647–2657, 2004.
 146. Halliwell B. Free radicals and antioxidants: A personal view. Nutr Rev 52: 253–265, 1994.
 147. Halliwell B. How to characterize an antioxidant: An update. Biochem Soc Symp 61: 73–101, 1995.
 148. Halliwell B, Gutteridge J. Free Radicals in Biology and Medicine. Oxford: Oxford Press, 2007: 936.
 149. Han D, Loukianoff S, McLaughlin L. Oxidative stress indices: Analytical aspects and significance. In: Sen CK, Packer L, Hanninen O, editors. Handbook of Oxidants and Antioxidants in Exercise. Amsterdam: Elsevier, 2000: 433–483.
 150. Han SN, Adolfsson O, Lee CK, Prolla TA, Ordovas J, Meydani SN. Vitamin E and gene expression in immune cells. Ann N Y Acad Sci 1031: 96–101, 2004.
 151. Hart JD, Dulhunty AF. Nitric oxide activates or inhibits skeletal muscle ryanodine receptors depending on its concentration, membrane potential and ligand binding. J Membr Biol 173: 227–236, 2000.
 152. Hawley JA, Zierath JR. Integration of metabolic and mitogenic signal transduction in skeletal muscle. Exerc Sport Sci Rev 32: 4–8, 2004.
 153. Haycock JW, Jones P, Harris JB, Mantle D. Differential susceptibility of human skeletal muscle proteins to free radical induced oxidative damage: A histochemical, immunocytochemical and electron microscopical study in vitro. Acta Neuropathol (Berl) 92: 331–340, 1996.
 154. Hearn AS, Tu C, Nick HS, Silverman DN. Characterization of the product‐inhibited complex in catalysis by human manganese superoxide dismutase. J Biol Chem 274: 24457–24460, 1999.
 155. Hellsten Y, Apple FS, Sjodin B. Effect of sprint cycle training on activities of antioxidant enzymes in human skeletal muscle. J Appl Physiol 81: 1484–1487, 1996.
 156. Hellsten Y, Nielsen JJ, Lykkesfeldt J, Bruhn M, Silveira L, Pilegaard H, Bangsbo J. Antioxidant supplementation enhances the exercise‐induced increase in mitochondrial uncoupling protein 3 and endothelial nitric oxide synthase mRNA content in human skeletal muscle. Free Radic Biol Med 43: 353–361, 2007.
 157. Hellsten Y, Svensson M, Sjodin B, Smith S, Christensen A, Richter EA, Bangsbo J. Allantoin formation and urate and glutathione exchange in human muscle during submaximal exercise. Free Radic Biol Med 31: 1313–1322, 2001.
 158. Hellsten Y, Tullson PC, Richter EA, Bangsbo J. Oxidation of urate in human skeletal muscle during exercise. Free Radic Biol Med 22: 169–174, 1997.
 159. Herrero A, Barja G. ADP‐regulation of mitochondrial free radical production is different with complex I‐ or complex II‐linked substrates: Implications for the exercise paradox and brain hypermetabolism. J Bioenerg Biomembr 29: 241–249, 1997.
 160. Heunks LM, Machiels HA, de Abreu R, Zhu XP, Van Der Heijden HF, Dekhuijzen PN. Free radicals in hypoxic rat diaphragm contractility: No role for xanthine oxidase. Am J Physiol Lung Cell Mol Physiol 281: L1402–L1412, 2001.
 161. Heunks LM, Machiels HA, Dekhuijzen PN, Prakash YS, Sieck GC. Nitric oxide affects sarcoplasmic calcium release in skeletal myotubes. J Appl Physiol 91: 2117–2124, 2001.
 162. Hidalgo C, Aracena P, Sanchez G, Donoso P. Redox regulation of calcium release in skeletal and cardiac muscle. Biol Res 35: 183–193, 2002.
 163. Hidalgo C, Sanchez G, Barrientos G, Aracena‐Parks P. A transverse tubule NADPH oxidase activity stimulates calcium release from isolated triads via ryanodine receptor type 1 S ‐glutathionylation. J Biol Chem 281: 26473–26482, 2006.
 164. Higuchi M, Cartier LJ, Chen M, Holloszy JO. Superoxide dismutase and catalase in skeletal muscle: Adaptive response to exercise. J Gerontol 40: 281–286, 1985.
 165. Hirschfield W, Moody MR, O'Brien WE, Gregg AR, Bryan RM Jr, Reid MB. Nitric oxide release and contractile properties of skeletal muscles from mice deficient in type III NOS. Am J Physiol Regul Integr Comp Physiol 278: R95–R100, 2000.
 166. Ho RC, Hirshman MF, Li Y, Cai D, Farmer JR, Aschenbach WG, Witczak CA, Shoelson SE, Goodyear LJ. Regulation of IkappaB kinase and NF‐kappaB in contracting adult rat skeletal muscle. Am J Physiol Cell Physiol 289: C794–C801, 2005.
 167. Ho YS, Howard AJ, Crapo JD. Molecular structure of a functional rat gene for manganese‐containing superoxide dismutase. Am J Respir Cell Mol Biol 4: 278–286, 1991.
 168. Hoffmann E, Thiefes A, Buhrow D, Dittrich‐Breiholz O, Schneider H, Resch K, Kracht M. MEK1‐dependent delayed expression of Fos‐related antigen‐1 counteracts c‐Fos and p65 NF‐kappaB‐mediated interleukin‐8 transcription in response to cytokines or growth factors. J Biol Chem 280: 9706–9718, 2005.
 169. Hollander J, Bejma J, Ookawara T, Ohno H, Ji LL. Superoxide dismutase gene expression in skeletal muscle: Fiber‐specific effect of age. Mech Ageing Dev 116: 33–45, 2000.
 170. Hollander J, Fiebig R, Gore M, Ookawara T, Ohno H, Ji LL. Superoxide dismutase gene expression is activated by a single bout of exercise in rat skeletal muscle. Pflugers Arch 442: 426–434, 2001.
 171. Holmgren A. Hydrogen donor system for Escherichia coli ribonucleoside‐diphosphate reductase dependent upon glutathione. Proc Natl Acad Sci U S A 73: 2275–2279, 1976.
 172. Holmgren A. Thioredoxin. Annu Rev Biochem 54: 237–271, 1985.
 173. Holmgren A. Thioredoxin and glutaredoxin systems. J Biol Chem 264: 13963–13966, 1989.
 174. Holmgren A, Johansson C, Berndt C, Lonn ME, Hudemann C, Lillig CH. Thiol redox control via thioredoxin and glutaredoxin systems. Biochem Soc Trans 33: 1375–1377, 2005.
 175. Hood DA, Irrcher I, Ljubicic V, Joseph AM. Coordination of metabolic plasticity in skeletal muscle. J Exp Biol 209: 2265–2275, 2006.
 176. Howell RR, Wyngaarden JB. On the mechanism of peroxidation of uric acids by hemoproteins. J Biol Chem 235: 3544–3550, 1960.
 177. Hunter RB, Stevenson E, Koncarevic A, Mitchell‐Felton H, Essig DA, Kandarian SC. Activation of an alternative NF‐kappaB pathway in skeletal muscle during disuse atrophy. FASEB J 16: 529–538, 2002.
 178. Hwang ES, Kim GH. Biomarkers for oxidative stress status of DNA, lipids, and proteins in vitro and in vivo cancer research. Toxicology 229: 1–10, 2007.
 179. Iemitsu M, Maeda S, Jesmin S, Otsuki T, Kasuya Y, Miyauchi T. Activation pattern of MAPK signaling in the hearts of trained and untrained rats following a single bout of exercise. J Appl Physiol 101: 151–163, 2006.
 180. Irrcher I, Adhihetty PJ, Sheehan T, Joseph AM, Hood DA. PPARgamma coactivator‐1alpha expression during thyroid hormone‐ and contractile activity‐induced mitochondrial adaptations. Am J Physiol Cell Physiol 284: C1669–C1677, 2003.
 181. Jackson MJ. Free radicals in skin and muscle: Damaging agents or signals for adaptation? Proc Nutr Soc 58: 673–676, 1999.
 182. Jackson MJ, Edwards RH, Symons MC. Electron spin resonance studies of intact mammalian skeletal muscle. Biochim Biophys Acta 847: 185–190, 1985.
 183. Jackson MJ, Khassaf M, Vasilaki A, McArdle F, McArdle A. Vitamin E and the oxidative stress of exercise. Ann N Y Acad Sci 1031: 158–168, 2004.
 184. Jackson MJ, Pye D, Palomero J. The production of reactive oxygen and nitrogen species by skeletal muscle. J Appl Physiol 102: 1664–1670, 2007.
 185. Janero DR. Therapeutic potential of vitamin E in the pathogenesis of spontaneous atherosclerosis. Free Radic Biol Med 11: 129–144, 1991.
 186. Javesghani D, Magder SA, Barreiro E, Quinn MT, Hussain SN. Molecular characterization of a superoxide‐generating NAD(P)H oxidase in the ventilatory muscles. Am J Respir Crit Care Med 165: 412–418, 2002.
 187. Ji L, Leeuwenburgh C. Exercise and glutathione. In: Somani S, editor. Pharmocology in Exercise and Sports. Boca Raton: CRC Press, 1995: 97–123.
 188. Ji LL. Exercise and oxidative stress: Role of the cellular antioxidant systems. Exerc Sport Sci Rev 23: 135–166, 1995.
 189. Ji LL. Antioxidants and oxidative stress in exercise. Proc Soc Exp Biol Med 222: 283–292, 1999.
 190. Ji LL. Exercise at old age: Does it increase or alleviate oxidative stress? Ann N Y Acad Sci 928: 236–247, 2001.
 191. Ji LL. Modulation of skeletal muscle antioxidant defense by exercise: Role of redox signaling. Free Radic Biol Med 44: 142–152, 2008.
 192. Ji LL, Gomez‐Cabrera MC, Steinhafel N, Vina J. Acute exercise activates nuclear factor (NF)‐kappaB signaling pathway in rat skeletal muscle. FASEB J 18: 1499–1506, 2004.
 193. Ji LL, Gomez‐Cabrera MC, Vina J. Exercise and hormesis: Activation of cellular antioxidant signaling pathway. Ann N Y Acad Sci 1067: 425–435, 2006.
 194. Ji LL, Stratman FW, Lardy HA. Antioxidant enzyme systems in rat liver and skeletal muscle. Influences of selenium deficiency, chronic training, and acute exercise. Arch Biochem Biophys 263: 150–160, 1988.
 195. Ji LLaJH. Antioxidant defense: Effects of aging and exercise. In: Radak Z, editor. Free Radicals in Exercise and Aging. Champaign: Human Kinetics, 2000: 35–72.
 196. Jiang B, Xu S, Hou X, Pimentel DR, Brecher P, Cohen RA. Temporal control of NF‐kappaB activation by ERK differentially regulates interleukin‐1beta‐induced gene expression. J Biol Chem 279: 1323–1329, 2004.
 197. Jones D. Radical free biology of oxidative stress. Am J Physiol Cell Physiol 295: C849–C868, 2008.
 198. Jones DP. Redefining oxidative stress. Antioxid Redox Signal 8: 1865–1879, 2006.
 199. Judge AR, Dodd SL. Xanthine oxidase and activated neutrophils cause oxidative damage to skeletal muscle after contractile claudication. Am J Physiol Heart Circ Physiol 286: H252–H256, 2004.
 200. Kagan VE, Shvedova A, Serbinova E, Khan S, Swanson C, Powell R, Packer L. Dihydrolipoic acid—a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals. Biochem Pharmacol 44: 1637–1649, 1992.
 201. Kaikkonen J, Kosonen L, Nyyssonen K, Porkkala‐Sarataho E, Salonen R, Korpela H, Salonen JT. Effect of combined coenzyme Q10 and d‐alpha‐tocopheryl acetate supplementation on exercise‐induced lipid peroxidation and muscular damage: A placebo‐controlled double‐blind study in marathon runners. Free Radic Res 29: 85–92, 1998.
 202. Kaneko M, Suzuki H, Masuda H, Yuan G, Hayashi H, Kobayashi A, Yamazaki N. [Effects of oxygen free radicals on Ca2+ binding to cardiac troponin]. Jpn Circ J 56 Suppl 5: 1288–1290, 1992.
 203. Kang C, O'Moore KM, Dickman JR, Ji LL. Exercise activation of muscle peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha signaling is redox sensitive. Free Radic Biol Med 47: 1394–1400, 2009.
 204. Kang SW, Rhee SG, Chang TS, Jeong W, Choi MH. 2‐Cys peroxiredoxin function in intracellular signal transduction: Therapeutic implications. Trends Mol Med 11: 571–578, 2005.
 205. Kanter MM. Free radicals, exercise, and antioxidant supplementation. Int J Sport Nutr 4: 205–220, 1994.
 206. Kanter MM, Williams MH. Antioxidants, carnitine, and choline as putative ergogenic aids. Int J Sport Nutr 5 Suppl: S120–131, 1995.
 207. Karanth J, Kumar R, Jeevaratnam K. Response of antioxidant system in rats to dietary fat and physical activity. Indian J Physiol Pharmacol 48: 446–452, 2004.
 208. Kasai H. Analysis of a form of oxidative DNA damage, 8‐hydroxy‐2'‐deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res 387: 147–163, 1997.
 209. Kefaloyianni E, Gaitanaki C, Beis I. ERK1/2 and p38‐MAPK signalling pathways, through MSK1, are involved in NF‐kappaB transactivation during oxidative stress in skeletal myoblasts. Cell Signal 18: 2238–2251, 2006.
 210. Kelly GS. Clinical applications of N‐acetylcysteine. Altern Med Rev 3: 114–127, 1998.
 211. Khanna S, Atalay M, Lodge JK, Laaksonen DE, Roy S, Hanninen O, Packer L, Sen CK. Skeletal muscle and liver lipoyllysine content in response to exercise, training and dietary alpha‐lipoic acid supplementation. Biochem Mol Biol Int 46: 297–306, 1998.
 212. Khassaf M, McArdle A, Esanu C, Vasilaki A, McArdle F, Griffiths RD, Brodie DA, Jackson MJ. Effect of vitamin C supplements on antioxidant defence and stress proteins in human lymphocytes and skeletal muscle. J Physiol 549: 645–652, 2003.
 213. Khawli FA, Reid MB. N‐acetylcysteine depresses contractile function and inhibits fatigue of diaphragm in vitro. J Appl Physiol 77: 317–324, 1994.
 214. Kim K, Kim IH, Lee KY, Rhee SG, Stadtman ER. The isolation and purification of a specific “protector” protein which inhibits enzyme inactivation by a thiol/Fe(III)/O2 mixed‐function oxidation system. J Biol Chem 263: 4704–4711, 1988.
 215. Kim K, Rhee SG, Stadtman ER. Nonenzymatic cleavage of proteins by reactive oxygen species generated by dithiothreitol and iron. J Biol Chem 260: 15394–15397, 1985.
 216. Kim YH, Park KH, Rho HM. Transcriptional activation of the Cu,Zn‐superoxide dismutase gene through the AP2 site by ginsenoside Rb2 extracted from a medicinal plant, Panax ginseng. J Biol Chem 271: 24539–24543, 1996.
 217. Kininggham K, Xu Y, Daosukho C, Popova B, and St. Clair D. Nuclear Factor κB‐dependent mechanism coordinate the synergistic effect of PMA and cytokines on the induction of superoxide dismutase 2. Biochem J 353: 147–156, 2001.
 218. Kirkman HN, Gaetani GF. Mammalian catalase: A venerable enzyme with new mysteries. Trends Biochem Sci 32: 44–50, 2007.
 219. Klingenberg M, Huang SG. Structure and function of the uncoupling protein from brown adipose tissue. Biochim Biophys Acta 1415: 271–296, 1999.
 220. Kobzik L, Reid MB, Bredt DS, Stamler JS. Nitric oxide in skeletal muscle. Nature 372: 546–548, 1994.
 221. Kobzik L, Stringer B, Balligand JL, Reid MB, Stamler JS. Endothelial type nitric oxide synthase in skeletal muscle fibers: Mitochondrial relationships. Biochem Biophys Res Commun 211: 375–381, 1995.
 222. Konig D, Wagner KH, Elmadfa I, Berg A. Exercise and oxidative stress: Significance of antioxidants with reference to inflammatory, muscular, and systemic stress. Exerc Immunol Rev 7: 108–133, 2001.
 223. Koren A, Sauber C, Sentjurc M, Schara M. Free radicals in tetanic activity of isolated skeletal muscle. Comp Biochem Physiol B 74: 633–635, 1983.
 224. Kozlov AV, Szalay L, Umar F, Kropik K, Staniek K, Niedermuller H, Bahrami S, Nohl H. Skeletal muscles, heart, and lung are the main sources of oxygen radicals in old rats. Biochim Biophys Acta 1740: 382–389, 2005.
 225. Krauss S, Zhang CY, Lowell BB. The mitochondrial uncoupling‐protein homologues. Nat Rev Mol Cell Biol 6: 248–261, 2005.
 226. Kretzschmar M, Muller D. Aging, training and exercise. review of effects on plasma glutathione and lipid peroxides A. Sports Med 15: 196–209, 1993.
 227. Krinsky NI. The antioxidant and biological properties of the carotenoids. Ann N Y Acad Sci 854: 443–447, 1998.
 228. Lambertucci RH, Levada‐Pires AC, Rossoni LV, Curi R, Pithon‐Curi TC. Effects of aerobic exercise training on antioxidant enzyme activities and mRNA levels in soleus muscle from young and aged rats. Mech Ageing Dev 128: 267–275, 2007.
 229. Lau KS, Grange RW, Chang WJ, Kamm KE, Sarelius I, Stull JT. Skeletal muscle contractions stimulate cGMP formation and attenuate vascular smooth muscle myosin phosphorylation via nitric oxide. FEBS Lett 431: 71–74, 1998.
 230. Laughlin MH, Simpson T, Sexton WL, Brown OR, Smith JK, Korthuis RJ. Skeletal muscle oxidative capacity, antioxidant enzymes, and exercise training. J Appl Physiol 68: 2337–2343, 1990.
 231. Lawler JM, Demaree SR. Relationship between NADP‐specific isocitrate dehydrogenase and glutathione peroxidase in aging rat skeletal muscle. Mech Ageing Dev 122: 291–304, 2001.
 232. Lawler JM, Kwak HB, Song W, Parker JL. Exercise training reverses downregulation of HSP70 and antioxidant enzymes in porcine skeletal muscle after chronic coronary artery occlusion. Am J Physiol Regul Integr Comp Physiol 291: R1756–R1763, 2006.
 233. Lawler JM, Powers SK, Criswell DS. Inducibility of NADP‐specific isocitrate dehydrogenase with endurance training in skeletal muscle. Acta Physiol Scand 149: 177–181, 1993.
 234. Lawler JM, Powers SK, Van Dijk H, Visser T, Kordus MJ, Ji LL. Metabolic and antioxidant enzyme activities in the diaphragm: Effects of acute exercise. Respir Physiol 96: 139–149, 1994.
 235. Lawson JA, Rokach J, FitzGerald GA. Isoprostanes: Formation, analysis and use as indices of lipid peroxidation in vivo. J Biol Chem 274: 24441–24444, 1999.
 236. Leeuwenburgh C, Fiebig R, Chandwaney R, Ji LL. Aging and exercise training in skeletal muscle: Responses of glutathione and antioxidant enzyme systems. Am J Physiol 267: R439–R445, 1994.
 237. Leeuwenburgh C, Hollander J, Leichtweis S, Griffiths M, Gore M, Ji LL. Adaptations of glutathione antioxidant system to endurance training are tissue and muscle fiber specific. Am J Physiol 272: R363–R369, 1997.
 238. Li JM, Shah AM. Endothelial cell superoxide generation: Regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287: R1014–R1030, 2004.
 239. Li N, Karin M. Is NF‐kappaB the sensor of oxidative stress? FASEB J 13: 1137–1143, 1999.
 240. Li Q, Engelhardt JF. Interleukin‐1beta induction of NFkappaB is partially regulated by H2O2‐mediated activation of NFkappaB‐inducing kinase. J Biol Chem 281: 1495–1505, 2006.
 241. Ljubicic V, Adhihetty PJ, Hood DA. Role of UCP3 in state 4 respiration during contractile activity‐induced mitochondrial biogenesis. J Appl Physiol 97: 976–983, 2004.
 242. Long YC, Widegren U, Zierath JR. Exercise‐induced mitogen‐activated protein kinase signalling in skeletal muscle. Proc Nutr Soc 63: 227–232, 2004.
 243. Loschen G, Azzi A, Richter C, Flohe L. Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett 42: 68–72, 1974.
 244. Lundberg M, Johansson C, Chandra J, Enoksson M, Jacobsson G, Ljung J, Johansson M, Holmgren A. Cloning and expression of a novel human glutaredoxin (Grx2) with mitochondrial and nuclear isoforms. J Biol Chem 276: 26269–26275, 2001.
 245. Luo G, Hershko DD, Robb BW, Wray CJ, Hasselgren PO. IL‐1beta stimulates IL‐6 production in cultured skeletal muscle cells through activation of MAP kinase signaling pathway and NF‐kappa B. Am J Physiol Regul Integr Comp Physiol 284: R1249–R1254, 2003.
 246. Maehara K, Hasegawa T, Isobe KI. A NF‐kappaB p65 subunit is indispensable for activating manganese superoxide: Dismutase gene transcription mediated by tumor necrosis factor‐alpha. J Cell Biochem 77: 474–486, 2000.
 247. Maehara K, Oh‐Hashi K, Isobe KI. Early growth‐responsive‐1‐dependent manganese superoxide dismutase gene transcription mediated by platelet‐derived growth factor. FASEB J 15: 2025–2026, 2001.
 248. Malech HL, Gallin JI. Current concepts: Immunology. Neutrophils in human diseases. N Engl J Med 317: 687–694, 1987.
 249. Marechal G, Beckers‐Bleukx G. Effect of nitric oxide on the maximal velocity of shortening of a mouse skeletal muscle. Pflugers Arch 436: 906–913, 1998.
 250. Marechal G, Gailly P. Effects of nitric oxide on the contraction of skeletal muscle. Cell Mol Life Sci 55: 1088–1102, 1999.
 251. Marin E, Kretzschmar M, Arokoski J, Hanninen O, Klinger W. Enzymes of glutathione synthesis in dog skeletal muscles and their response to training. Acta Physiol Scand 147: 369–373, 1993.
 252. Marinov BS, Olojo RO, Xia R, Abramson JJ. Non‐thiol reagents regulate ryanodine receptor function by redox interactions that modify reactive thiols. Antioxid Redox Signal 9: 609–621, 2007.
 253. Martinez‐Galisteo E, Padilla CA, Holmgren A, Barcena JA. Characterization of mammalian thioredoxin reductase, thioredoxin and glutaredoxin by immunochemical methods. Comp Biochem Physiol B Biochem Mol Biol 111: 17–25, 1995.
 254. Matuszczak Y, Farid M, Jones J, Lansdowne S, Smith MA, Taylor AA, Reid MB. Effects of N‐acetylcysteine on glutathione oxidation and fatigue during handgrip exercise. Muscle Nerve 32: 633–638, 2005.
 255. McArdle A, Dillmann WH, Mestril R, Faulkner JA, Jackson MJ. Overexpression of HSP70 in mouse skeletal muscle protects against muscle damage and age‐related muscle dysfunction. Faseb J 18: 355–357, 2004.
 256. McArdle A, Jackson MJ. Exercise, oxidative stress and ageing. J Anat 197 Pt 4: 539–541, 2000.
 257. McArdle A, Pattwell D, Vasilaki A, Griffiths RD, Jackson MJ. Contractile activity‐induced oxidative stress: Cellular origin and adaptive responses. Am J Physiol Cell Physiol 280: C621–C627, 2001.
 258. McArdle F, Spiers S, Aldemir H, Vasilaki A, Beaver A, Iwanejko L, McArdle A, Jackson MJ. Preconditioning of skeletal muscle against contraction‐induced damage: The role of adaptations to oxidants in mice. J Physiol 561: 233–244, 2004.
 259. McClung J, Deruisseau K, Whidden M, Van Remmen H, Richardson A, Song W, Vrabas I, Powers SK. Overexpression of antioxidant enzymes in diaphragm muscle does not alter contraction‐induced fatigue or recovery. Exp Physiol 95: 222–231, 2010.
 260. McClung JM, Judge AR, Talbert EE, Powers SK. Calpain‐1 is required for hydrogen peroxide‐induced myotube atrophy. Am J Physiol 296: C363–C371, 2009.
 261. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244: 6049–6055, 1969.
 262. McKenna MJ, Medved I, Goodman CA, Brown MJ, Bjorksten AR, Murphy KT, Petersen AC, Sostaric S, Gong X. N‐acetylcysteine attenuates the decline in muscle Na+,K+‐pump activity and delays fatigue during prolonged exercise in humans. J Physiol 576: 279–288, 2006.
 263. McKenzie EC, Jose‐Cunilleras E, Hinchcliff KW, Holbrook TC, Royer C, Payton ME, Williamson K, Nelson S, Willard MD, Davis MS. Serum chemistry alterations in Alaskan sled dogs during five successive days of prolonged endurance exercise. J Am Vet Med Assoc 230: 1486–1492, 2007.
 264. Medved I, Brown MJ, Bjorksten AR, Leppik JA, Sostaric S, McKenna MJ. N‐acetylcysteine infusion alters blood redox status but not time to fatigue during intense exercise in humans. J Appl Physiol 94: 1572–1582, 2003.
 265. Medved I, Brown MJ, Bjorksten AR, McKenna MJ. Effects of intravenous N‐acetylcysteine infusion on time to fatigue and potassium regulation during prolonged cycling exercise. J Appl Physiol 96: 211–217, 2004.
 266. Medved I, Brown MJ, Bjorksten AR, Murphy KT, Petersen AC, Sostaric S, Gong X, McKenna MJ. N‐acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance‐trained individuals. J Appl Physiol 97: 1477–1485, 2004.
 267. Meijer AE. The histochemical localization of reduced glutathione in skeletal muscle under different pathophysiological conditions. Acta Histochem 90: 147–154, 1991.
 268. Meister AE, Anderson ME. Glutathione. Annu Rev Biochem 52: 711–760, 1983.
 269. Meyer M, Pahl HL, Baeuerle PA. Regulation of the transcription factors NF‐kappa B and AP‐1 by redox changes. Chem Biol Interact 91: 91–100, 1994.
 270. Mizuno M, Quistorff B, Theorell H, Theorell M, Chance B. Effects of oral supplementation of coenzyme Q10 on 31P‐NMR detected skeletal muscle energy metabolism in middle‐aged post‐polio subjects and normal volunteers. Mol Aspects Med 18 Suppl: S291–S298, 1997.
 271. Mohr S, Stamler JS, Brune B. Posttranslational modification of glyceraldehyde‐3‐phosphate dehydrogenase by S‐nitrosylation and subsequent NADH attachment. J Biol Chem 271: 4209–4214, 1996.
 272. Molina y Vedia L, McDonald B, Reep B, Brune B, Di Silvio M, Billiar TR, Lapetina EG. Nitric oxide‐induced S‐nitrosylation of glyceraldehyde‐3‐phosphate dehydrogenase inhibits enzymatic activity and increases endogenous ADP‐ribosylation. J Biol Chem 267: 24929–24932, 1992.
 273. Monteiro HP, Stern A. Redox modulation of tyrosine phosphorylation‐dependent signal transduction pathways. Free Radic Biol Med 21: 323–333, 1996.
 274. Moopanar TR, Allen DG. Reactive oxygen species reduce myofibrillar Ca2 +sensitivity in fatiguing mouse skeletal muscle at 37 degrees C. J Physiol 564: 189–199, 2005.
 275. Morre DJ. Quinone oxidoreductases of the plasma membrane. Methods Enzymol 378: 179–199, 2004.
 276. Muller FL, Liu Y, Van Remmen H. Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279: 49064–49073, 2004.
 277. Muralikrishna Adibhatla R, Hatcher JF. Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic Biol Med 40: 376–387, 2006.
 278. Nader GA, Esser KA. Intracellular signaling specificity in skeletal muscle in response to different modes of exercise. J Appl Physiol 90: 1936–1942, 2001.
 279. Negash S, Chen LT, Bigelow DJ, Squier TC. Phosphorylation of phospholamban by cAMP‐dependent protein kinase enhances interactions between Ca‐ATPase polypeptide chains in cardiac sarcoplasmic reticulum membranes. Biochemistry 35: 11247–11259, 1996.
 280. Nethery D, Callahan LA, Stofan D, Mattera R, DiMarco A, Supinski G. PLA(2) dependence of diaphragm mitochondrial formation of reactive oxygen species. J Appl Physiol 89: 72–80, 2000.
 281. Nethery D, Stofan D, Callahan L, DiMarco A, Supinski G. Formation of reactive oxygen species by the contracting diaphragm is PLA(2) dependent. J Appl Physiol 87: 792–800, 1999.
 282. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, Bracale R, Valerio A, Francolini M, Moncada S, Carruba MO. Mitochondrial biogenesis in mammals: The role of endogenous nitric oxide. Science 299: 896–899, 2003.
 283. Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E, Gustafsson T. PGC‐1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol 96: 189–194, 2004.
 284. Novelli GP, Bracciotti G, Falsini S. Spin‐trappers and vitamin E prolong endurance to muscle fatigue in mice. Free Radic Biol Med 8: 9–13, 1990.
 285. Nulton‐Persson AC, Szweda LI. Modulation of mitochondrial function by hydrogen peroxide. J Biol Chem 276: 23357–23361, 2001.
 286. Oba T, Ishikawa T, Murayama T, Ogawa Y, Yamaguchi M. H(2)O(2) and ethanol act synergistically to gate ryanodine receptor/calcium‐release channel. Am J Physiol Cell Physiol 279: C1366–1374, 2000.
 287. Oh‐ishi S, Kizaki T, Nagasawa J, Izawa T, Komabayashi T, Nagata N, Suzuki K, Taniguchi N, Ohno H. Effects of endurance training on superoxide dismutase activity, content and mRNA expression in rat muscle. Clin Exp Pharmacol Physiol 24: 326–332, 1997.
 288. Ohkuwa T, Sato Y, Naoi M. Glutathione status and reactive oxygen generation in tissues of young and old exercised rats. Acta Physiol Scand 159: 237–244, 1997.
 289. Ojuka EO, Jones TE, Han DH, Chen M, Holloszy JO. Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle. FASEB J 17: 675–681, 2003.
 290. Ong SH, Steiner AL. Localization of cyclic GMP and cyclic AMP in cardiac and skeletal muscle: Immunocytochemical demonstration. Science 195: 183–185, 1977.
 291. Oyanagui Y. Reevaluation of assay methods and establishment of kit for superoxide dismutase activity. Anal Biochem 142: 290–296, 1984.
 292. Packer JE, Slater TF, Willson RL. Direct observation of a free radical interaction between vitamin E and vitamin C. Nature 278: 737–738, 1979.
 293. Packer L. Protective role of vitamin E in biological systems. Am J Clin Nutr 53: 1050S–1055S, 1991.
 294. Packer L. Antioxidant properties of lipoic acid and its therapeutic effects in prevention of diabetes complications and cataracts. Ann N Y Acad Sci 738: 257–264, 1994.
 295. Packer L, Witt EH, Tritschler HJ. alpha‐Lipoic acid as a biological antioxidant. Free Radic Biol Med 19: 227–250, 1995.
 296. Pattwell DM, McArdle A, Morgan JE, Patridge TA, Jackson MJ. Release of reactive oxygen and nitrogen species from contracting skeletal muscle cells. Free Radic Biol Med 37: 1064–1072, 2004.
 297. Pedersen BK, Ostrowski K, Rohde T, Bruunsgaard H. The cytokine response to strenuous exercise. Can J Physiol Pharmacol 76: 505–511, 1998.
 298. Pereira B, Costa Rosa LF, Safi DA, Medeiros MH, Curi R, Bechara EJ. Superoxide dismutase, catalase, and glutathione peroxidase activities in muscle and lymphoid organs of sedentary and exercise‐trained rats. Physiol Behav 56: 1095–1099, 1994.
 299. Perkins WJ, Han YS, Sieck GC. Skeletal muscle force and actomyosin ATPase activity reduced by nitric oxide donor. J Appl Physiol 83: 1326–1332, 1997.
 300. Pessah IN, Feng W. Functional role of hyperreactive sulfhydryl moieties within the ryanodine receptor complex. Antioxid Redox Signal 2: 17–25, 2000.
 301. Plant DR, Lynch GS, Williams DA. Hydrogen peroxide modulates Ca2+‐activation of single permeabilized fibres from fast‐ and slow‐twitch skeletal muscles of rats. J Muscle Res Cell Motil 21: 747–752, 2000.
 302. Posterino GS, Cellini MA, Lamb GD. Effects of oxidation and cytosolic redox conditions on excitation‐contraction coupling in rat skeletal muscle. J Physio 547: 807–823, 2003.
 303. Powers S, Sen CK. Physiological antioxidants and exercise training. In: Sen CK, Packer L, Hanninen O, editors. Handbook of Oxidants and Antioxidants in Exercise. Amsterdam: Elsevier, 2000: 221–242.
 304. Powers SK, Smuder A, Kavazis A, Hudson MB. Experimental guidelines for studies designed to investigate the impact of antioxidant supplementation on exercise performance. Int J Sport Nutr Exerc Metab 20: 2–14, 2010
 305. Powers SK, Criswell D, Lawler J, Ji LL, Martin D, Herb RA, Dudley G. Influence of exercise and fiber type on antioxidant enzyme activity in rat skeletal muscle. Am J Physiol 266: R375–R380, 1994.
 306. Powers SK, Criswell D, Lawler J, Martin D, Ji LL, Herb RA, Dudley G. Regional training‐induced alterations in diaphragmatic oxidative and antioxidant enzymes. Respir Physiol 95: 227–237, 1994.
 307. Powers SK, DeCramer M, Gayan‐Ramirez G, Levine S. Pressure support ventilation attenuates ventilator‐induced protein modifications in the diaphragm. Critical care (London, England) 12: 191, 2008.
 308. Powers SK, DeRuisseau KC, Quindry J, Hamilton KL. Dietary antioxidants and exercise. J Sports Sci 22: 81–94, 2004.
 309. Powers SK, Duarte J, Kavazis AN, Talbert EE. Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp Physiol 95: 1–9, 2010.
 310. Powers SK, Hamilton K. Antioxidants and exercise. Clin Sports Med 18: 525–536, 1999.
 311. Powers SK, Jackson MJ. Exercise‐induced oxidative stress: Cellular mechanisms and impact on muscle force production. Physiol Rev 88: 1243–1276, 2008.
 312. Powers SK, Ji LL, Leeuwenburgh C. Exercise training‐induced alterations in skeletal muscle antioxidant capacity: A brief review. Med Sci Sports Exerc 31: 987–997, 1999.
 313. Powers SK, Lawler J, Criswell D, Lieu FK, Martin D. Aging and respiratory muscle metabolic plasticity: Effects of endurance training. J Appl Physiol 72: 1068–1073, 1992.
 314. Powers SK, Smuder AJ, Kavazis AN, Hudson MB. Experimental guidelines for studies designed to investigate the impact of antioxidant supplementation on exercise performance. Int J Sport Nutr Exerc Metab 20: 2–14, 2010.
 315. Prochniewicz E, Lowe DA, Spakowicz DJ, Higgins L, O'Conor K, Thompson LV, Ferrington DA, Thomas DD. Functional, structural, and chemical changes in myosin associated with hydrogen peroxide treatment of skeletal muscle fibers. Am J Physiol Cell Physiol 294: C613–C626, 2008.
 316. Pye D, Palomero J, Kabayo T, Jackson MJ. Real‐time measurement of nitric oxide in single mature mouse skeletal muscle fibres during contractions. J Physiol 581: 309–318, 2007.
 317. Quintanilha AT. Effects of physical exercise and/or vitamin E on tissue oxidative metabolism. Biochem Soc Trans 12: 403–404, 1984.
 318. Radak Z, Asano K, Inoue M, Kizaki T, Oh‐Ishi S, Suzuki K, Taniguchi N, Ohno H. Superoxide dismutase derivative reduces oxidative damage in skeletal muscle of rats during exhaustive exercise. J Appl Physiol 79: 129–135, 1995.
 319. Radak Z, Taylor AW, Ohno H, Goto S. Adaptation to exercise‐induced oxidative stress: From muscle to brain. Exerc Immunol Rev 7: 90–107, 2001.
 320. Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 16: 534–554, 2000.
 321. Ramires PR, Ji LL. Glutathione supplementation and training increases myocardial resistance to ischemia‐reperfusion in vivo. Am J Physiol Heart Circ Physiol 281: H679–H688, 2001.
 322. Reid MB. Role of nitric oxide in skeletal muscle: Synthesis, distribution and functional importance. Acta Physiol Scand 162: 401–409, 1998.
 323. Reid MB. Invited Review: Redox modulation of skeletal muscle contraction: What we know and what we don't. J Appl Physiol 90: 724–731, 2001a.
 324. Reid MB. Nitric oxide, reactive oxygen species, and skeletal muscle contraction. Med Sci Sports Exerc 33: 371–376, 2001b.
 325. Reid MB. Free radicals and muscle fatigue: Of ROS, canaries, and the IOC. Free Radic Biol Med 44: 169–179, 2008.
 326. Reid MB, Andrade FH, Balke CW, Esser KA. Redox mechanisms of muscle dysfunction in inflammatory disease. Phys Med Rehabil Clin N Am 16: 925–949, ix, 2005.
 327. Reid MB, Haack KE, Franchek KM, Valberg PA, Kobzik L, West MS. Reactive oxygen in skeletal muscle. I. Intracellular oxidant kinetics and fatigue in vitro. J Appl Physiol 73: 1797–1804, 1992.
 328. Reid MB, Khawli FA, Moody MR. Reactive oxygen in skeletal muscle. III. Contractility of unfatigued muscle. J Appl Physiol 75: 1081–1087, 1993.
 329. Reid MB, Kobzik L, Bredt DS, Stamler JS. Nitric oxide modulates excitation‐contraction coupling in the diaphragm. Comp Biochem Physiol A Mol Integr Physiol 119: 211–218, 1998.
 330. Reid MB, Moody MR. Dimethyl sulfoxide depresses skeletal muscle contractility. J Appl Physiol 76: 2186–2190, 1994.
 331. Reid MB, Shoji T, Moody MR, Entman ML. Reactive oxygen in skeletal muscle. II. Extracellular release of free radicals. J Appl Physiol 73: 1805–1809, 1992.
 332. Reid MB, Stokic DS, Koch SM, Khawli FA, Leis AA. N‐acetylcysteine inhibits muscle fatigue in humans. J Clin Invest 94: 2468–2474, 1994.
 333. Rhee SG, Chae HZ, Kim K. Peroxiredoxins: A historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med 38: 1543–1552, 2005.
 334. Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS, Woo HA. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr Opin Cell Biol 17: 183–189, 2005.
 335. Rhee SG, Yang KS, Kang SW, Woo HA, Chang TS. Controlled elimination of intracellular H(2)O(2): Regulation of peroxiredoxin, catalase, and glutathione peroxidase via post‐translational modification. Antioxid Redox Signal 7: 619–626, 2005.
 336. Richmonds CR, Kaminski HJ. Nitric oxide synthase expression and effects of nitric oxide modulation on contractility of rat extraocular muscle. Faseb J 15: 1764–1770, 2001.
 337. Roberts LJ, Morrow JD. Measurement of F(2)‐isoprostanes as an index of oxidative stress in vivo. Free Radic Biol Med 28: 505–513, 2000.
 338. Rokitzki L, Logemann E, Huber G, Keck E, Keul J. alpha‐Tocopherol supplementation in racing cyclists during extreme endurance training. Int J Sport Nutr 4: 253–264, 1994.
 339. Rosenfeldt F, Hilton D, Pepe S, Krum H. Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure. Biofactors 18: 91–100, 2003.
 340. Roy S, Packer L. Redox regulation of cell functions by alpha‐lipoate: Biochemical and molecular aspects. Biofactors 8: 17–21, 1998.
 341. Rudnick J, Puttmann B, Tesch PA, Alkner B, Schoser BG, Salanova M, Kirsch K, Gunga HC, Schiffl G, Luck G, Blottner D. Differential expression of nitric oxide synthases (NOS 1‐3) in human skeletal muscle following exercise countermeasure during 12 weeks of bed rest. Faseb J 18: 1228–1230, 2004.
 342. Ryder JW, Fahlman R, Wallberg‐Henriksson H, Alessi DR, Krook A, Zierath JR. Effect of contraction on mitogen‐activated protein kinase signal transduction in skeletal muscle. Involvement of the mitogen‐ and stress‐activated protein kinase 1. J Biol Chem 275: 1457–1462, 2000.
 343. Sabine B, Willenbrock R, Haase H, Karczewski P, Wallukat G, Dietz R, Krause EG. Cyclic GMP‐mediated phospholamban phosphorylation in intact cardiomyocytes. Biochem Biophys Res Commun 214: 75–80, 1995.
 344. Sachdev S, Davies KJ. Production, detection, and adaptive responses to free radicals in exercise. Free Radic Biol Med 44: 215–223, 2008.
 345. Sakamoto K, Goodyear LJ. Invited review: Intracellular signaling in contracting skeletal muscle. J Appl Physiol 93: 369–383, 2002.
 346. Salama G, Abramson JJ, Pike GK. Sulphydryl reagents trigger Ca2+ release from the sarcoplasmic reticulum of skinned rabbit psoas fibres. J Physiol 454: 389–420, 1992.
 347. Salama G, Menshikova EV, Abramson JJ. Molecular interaction between nitric oxide and ryanodine receptors of skeletal and cardiac sarcoplasmic reticulum. Antioxid Redox Signal 2: 5–16, 2000.
 348. Sale DG. Influence of exercise and training on motor unit activation. Exerc Sport Sci Rev 15: 95–151, 1987.
 349. Salminen A, Vihko V. Endurance training reduces the susceptibility of mouse skeletal muscle to lipid peroxidation in vitro. Acta Physiol Scand 117: 109–113, 1983.
 350. Salvador A, Sousa J, Pinto RE. Hydroperoxyl, superoxide and pH gradients in the mitochondrial matrix: A theoretical assessment. Free Radic Biol Med 31: 1208–1215, 2001.
 351. Scarlett DJ, Herst PM, Berridge MV. Multiple proteins with single activities or a single protein with multiple activities: The conundrum of cell surface NADH oxidoreductases. Biochim Biophys Acta 1708: 108–119, 2005.
 352. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88: 611–638, 2008.
 353. Schaffer S, Muller WE, Eckert GP. Tocotrienols: Constitutional effects in aging and disease. J Nutr 135: 151–154, 2005.
 354. Scherer NM, Deamer DW. Oxidative stress impairs the function of sarcoplasmic reticulum by oxidation of sulfhydryl groups in the Ca2+‐ATPase. Arch Biochem Biophys 246: 589–601, 1986.
 355. Schreck R, Albermann K, Baeuerle PA. Nuclear factor kappa B: An oxidative stress‐responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun 17: 221–237, 1992.
 356. Schulte I, Bektas H, Klempnauer J, Borlak J. Vitamin E in heart transplantation: Effects on cardiac gene expression. Transplantation 81: 736–745, 2006.
 357. Schulze PC, Gielen S, Schuler G, Hambrecht R. Chronic heart failure and skeletal muscle catabolism: Effects of exercise training. Int J Cardiol 85: 141–149, 2002.
 358. Sekhar KR, Meredith MJ, Kerr LD, Soltaninassab SR, Spitz DR, Xu ZQ, Freeman ML. Expression of glutathione and gamma‐glutamylcysteine synthetase mRNA is Jun dependent. Biochem Biophys Res Commun 234: 588–593, 1997.
 359. Sen CK. Oxidants and antioxidants in exercise. J Appl Physiol 79: 675–686, 1995.
 360. Sen CK. Update on thiol status and supplements in physical exercise. Can J Appl Physiol 26 Suppl: S4–S12, 2001.
 361. Sen CK, Khanna S, Reznick AZ, Roy S, Packer L. Glutathione regulation of tumor necrosis factor‐alpha‐induced NF‐kappa B activation in skeletal muscle‐derived L6 cells. Biochem Biophys Res Commun 237: 645–649, 1997.
 362. Sen CK, Marin E, Kretzschmar M, Hanninen O. Skeletal muscle and liver glutathione homeostasis in response to training, exercise, and immobilization. J Appl Physiol 73: 1265–1272, 1992.
 363. Sen CK, Packer L. Antioxidant and redox regulation of gene transcription. Faseb J 10: 709–720, 1996.
 364. Sen CK, Rankinen T, Vaisanen S, Rauramaa R. Oxidative stress after human exercise: Effect of N‐acetylcysteine supplementation. J Appl Physiol 76: 2570–2577, 1994.
 365. Sevanian A, Davies KJ, Hochstein P. Conservation of vitamin C by uric acid in blood. J Free Radic Biol Med 1: 117–124, 1985.
 366. Sharpe P. Oxidative stress and exercise: Need for antioxidant supplementation? Br J Sports Med 33: 298–299, 1999.
 367. Shimomura Y, Suzuki M, Sugiyama S, Hanaki Y, Ozawa T. Protective effect of coenzyme Q10 on exercise‐induced muscular injury. Biochem Biophys Res Commun 176: 349–355, 1991.
 368. Shindoh C, DiMarco A, Thomas A, Manubay P, Supinski G. Effect of N‐acetylcysteine on diaphragm fatigue. J Appl Physiol 68: 2107–2113, 1990.
 369. Sies H. Oxidative Stress. London: Academic press, 1985.
 370. Sies H, Cadenas E. Oxidative stress: Damage to intact cells and organs. Philos Trans R Soc Lond B Biol Sci 311: 617–631, 1985.
 371. Sies H, Jones DP. Oxidative Stress. In: Fink G., editor. Encyclopaedia of stress. San Diego, Elsevier, 2007: 45–48.
 372. Simic M, Jovanociv S. Antioxidantion mechanisms of uric acid. J Am Chem Soc 111: 5778, 1989.
 373. Smith MA, Reid MB. Redox modulation of contractile function in respiratory and limb skeletal muscle. Respir Physiol Neurobiol 151: 229–241, 2006.
 374. Snider IP, Bazzarre TL, Murdoch SD, Goldfarb A. Effects of coenzyme athletic performance system as an ergogenic aid on endurance performance to exhaustion. Int J Sport Nutr 2: 272–286, 1992.
 375. Stahl W, Sies H. Antioxidant activity of carotenoids. Mol Aspects Med 24: 345–351, 2003.
 376. Stamler JS, Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol Rev 81: 209–237, 2001.
 377. Starnes JW, Cantu G, Farrar RP, Kehrer JP. Skeletal muscle lipid peroxidation in exercised and food‐restricted rats during aging. J Appl Physiol 67: 69–75, 1989.
 378. Stocker R. Antioxidant activities of bile pigments. Antioxid Redox Signal 6: 841–849, 2004.
 379. Stocker R, Glazer AN, Ames BN. Antioxidant activity of albumin‐bound bilirubin. Proc Natl Acad Sci U S A 84: 5918–5922, 1987.
 380. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 235: 1043–1046, 1987.
 381. St‐Pierre J, Buckingham JA, Roebuck SJ, Brand MD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277: 44784–44790, 2002.
 382. St‐Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM. Suppression of reactive oxygen species and neurodegeneration by the PGC‐1 transcriptional coactivators. Cell 127: 397–408, 2006.
 383. Sun J, Xu L, Eu JP, Stamler JS, Meissner G. Classes of thiols that influence the activity of the skeletal muscle calcium release channel. J Biol Chem 276: 15625–15630, 2001.
 384. Supinski G. Free radical induced respiratory muscle dysfunction. Mol Cell Biochem 179: 99–110, 1998.
 385. Supinski GS, Callahan LA. Free radical‐mediated skeletal muscle dysfunction in inflammatory conditions. J Appl Physiol 102: 2056–2063, 2007.
 386. Supinski GS, Stofan D, Ciufo R, DiMarco A. N‐acetylcysteine administration alters the response to inspiratory loading in oxygen‐supplemented rats. J Appl Physiol 82: 1119–1125, 1997.
 387. Suzuki K, Ohno H, Oh‐ishi S, Kizaki T, Ookawara T, Fukii J, Radak A, Taniguchi N. Superoxide dismutases in exercise and disease. In: Sen CK, Packer L, Hanninen O, editors. Handbook of Oxidants and Antioxidants and Exercise. Amsterdam: Elsevier, 2000: 243–295.
 388. Svensson M, Malm C, Tonkonogi M, Ekblom B, Sjodin B, Sahlin K. Effect of Q10 supplementation on tissue Q10 levels and adenine nucleotide catabolism during high‐intensity exercise. Int J Sport Nutr 9: 166–180, 1999.
 389. Taylor RP, Starnes JW. Age, cell signalling and cardioprotection. Acta Physiol Scand 178: 107–116, 2003.
 390. Terada S, Goto M, Kato M, Kawanaka K, Shimokawa T, Tabata I. Effects of low‐intensity prolonged exercise on PGC‐1 mRNA expression in rat epitrochlearis muscle. Biochem Biophys Res Commun 296: 350–354, 2002.
 391. Tidball JG, Lavergne E, Lau KS, Spencer MJ, Stull JT, Wehling M. Mechanical loading regulates NOS expression and activity in developing and adult skeletal muscle. Am J Physiol 275: C260–266, 1998.
 392. Tiidus PM, Houston ME. Vitamin E status and response to exercise training. Sports Med 20: 12–23, 1995.
 393. Tiidus PM, Pushkarenko J, Houston ME. Lack of antioxidant adaptation to short‐term aerobic training in human muscle. Am J Physiol 271: R832–R836, 1996.
 394. Travaline JM, Sudarshan S, Roy BG, Cordova F, Leyenson V, Criner GJ. Effect of N‐acetylcysteine on human diaphragm strength and fatigability. Am J Respir Crit Care Med 156: 1567–1571, 1997.
 395. Urso ML, Clarkson PM. Oxidative stress, exercise, and antioxidant supplementation. Toxicology 189: 41–54, 2003.
 396. van Ginneken MM, de Graaf‐Roelfsema E, Keizer HA, van Dam KG, Wijnberg ID, Van Der Kolk JH, van Breda E. Effect of exercise on activation of the p38 mitogen‐activated protein kinase pathway, c‐Jun NH2 terminal kinase, and heat shock protein 27 in equine skeletal muscle. Am J Vet Res 67: 837–844, 2006.
 397. Van Remmen H, Hamilton ML, Richardson A. Oxidative damage to DNA and aging. Exerc Sport Sci Rev 31: 149–153, 2003.
 398. Vasilaki A, Mansouri A, Remmen H, Van Der Meulen JH, Larkin L, Richardson AG, McArdle A, Faulkner JA, Jackson MJ. Free radical generation by skeletal muscle of adult and old mice: Effect of contractile activity. Aging Cell 5: 109–117, 2006.
 399. Vassilakopoulos T, Deckman G, Kebbewar M, Rallis G, Harfouche R, Hussain SN. Regulation of nitric oxide production in limb and ventilatory muscles during chronic exercise training. Am J Physiol Lung Cell Mol Physiol 284: L452–L457, 2003.
 400. Venditti P, Di Meo S. Antioxidants, tissue damage, and endurance in trained and untrained young male rats. Arch Biochem Biophys 331: 63–68, 1996.
 401. Venditti P, Di Meo S. Effect of training on antioxidant capacity, tissue damage, and endurance of adult male rats. Int J Sports Med 18: 497–502, 1997.
 402. Vincent HK, Powers SK, Demirel HA, Coombes JS, Naito H. Exercise training protects against contraction‐induced lipid peroxidation in the diaphragm. Eur J Appl Physiol Occup Physiol 79: 268–273, 1999.
 403. Vincent HK, Powers SK, Stewart DJ, Demirel HA, Shanely RA, Naito H. Short‐term exercise training improves diaphragm antioxidant capacity and endurance. Eur J Appl Physiol 81: 67–74, 2000.
 404. Viner RI, Krainev AG, Williams TD, Schoneich C, Bigelow DJ. Identification of oxidation‐sensitive peptides within the cytoplasmic domain of the sarcoplasmic reticulum Ca2+‐ATPase. Biochemistry 36: 7706–7716, 1997.
 405. Viner RI, Williams TD, Schoneich C. Nitric oxide‐dependent modification of the sarcoplasmic reticulum Ca‐ATPase: Localization of cysteine target sites. Free Radic Biol Med 29: 489–496, 2000.
 406. Westerblad H, Allen DG, Lannergren J. Muscle fatigue: Lactic acid or inorganic phosphate the major cause? News Physiol Sci 17: 17–21, 2002.
 407. Whidden MA, McClung JM, Falk DJ, Hudson MB, Smuder AJ, Nelson WB, Powers SK. Xanthine oxidase contributes to mechanical ventilation‐induced diaphragmatic oxidative stress and contractile dysfunction. J Appl Physiol 106: 385–394, 2009.
 408. Wierzba TH, Olek RA, Fedeli D, Falcioni G. Lymphocyte DNA damage in rats challenged with a single bout of strenuous exercise. J Physiol Pharmacol 57 Suppl 10: 115–131, 2006.
 409. Wingert RA, Galloway JL, Barut B, Foott H, Fraenkel P, Axe JL, Weber GJ, Dooley K, Davidson AJ, Schmid B, Paw BH, Shaw GC, Kingsley P, Palis J, Schubert H, Chen O, Kaplan J, Zon LI. Deficiency of glutaredoxin 5 reveals Fe‐S clusters are required for vertebrate haem synthesis. Nature 436: 1035–1039, 2005.
 410. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr 134: 489–492, 2004.
 411. Xia R, Webb JA, Gnall LL, Cutler K, Abramson JJ. Skeletal muscle sarcoplasmic reticulum contains a NADH‐dependent oxidase that generates superoxide. Am J Physiol Cell Physiol 285: C215–C221, 2003.
 412. Xu KY, Zweier JL, Becker LC. Hydroxyl radical inhibits sarcoplasmic reticulum Ca(2+)‐ATPase function by direct attack on the ATP binding site. Circ Res 80: 76–81, 1997.
 413. Yamada T, Mishima T, Sakamoto M, Sugiyama M, Matsunaga S, Wada M. Oxidation of myosin heavy chain and reduction in force production in hyperthyroid rat soleus. J Appl Physiol 100: 1520–1526, 2006.
 414. Yi X, Maeda N. alpha‐Lipoic acid prevents the increase in atherosclerosis induced by diabetes in apolipoprotein E‐deficient mice fed high‐fat/low‐cholesterol diet. Diabetes 55: 2238–2244, 2006.
 415. Yoo HY, Chang MS, Rho HM. The activation of the rat copper/zinc superoxide dismutase gene by hydrogen peroxide through the hydrogen peroxide‐responsive element and by paraquat and heat shock through the same heat shock element. J Biol Chem 274: 23887–23892, 1999.
 416. Yoshioka J, Schreiter ER, Lee RT. Role of thioredoxin in cell growth through interactions with signaling molecules. Antioxid Redox Signal 8: 2143–2151, 2006.
 417. Yu BP. Cellular defenses against damage from reactive oxygen species. Physiol Rev 74: 139–162, 1994.
 418. Zable AC, Favero TG, Abramson JJ. Glutathione modulates ryanodine receptor from skeletal muscle sarcoplasmic reticulum. for redox regulation of the Ca2+ release mechanism Evidence. J Biol Chem 272: 7069–7077, 1997.
 419. Zamocky M, Koller F. Understanding the structure and function of catalases: Clues from molecular evolution and in vitro mutagenesis. Prog Biophys Mol Biol 72: 19–66, 1999.
 420. Zerba E, Komorowski TE, Faulkner JA. Free radical injury to skeletal muscles of young, adult, and old mice. Am J Physiol 258: C429–C435, 1990.
 421. Zhang JZ, Wu Y, Williams BY, Rodney G, Mandel F, Strasburg GM, Hamilton SL. Oxidation of the skeletal muscle Ca2+ release channel alters calmodulin binding. Am J Physiol 276: C46–C53, 1999.
 422. Zhang Q, Scholz PM, He Y, Tse J, Weiss HR. Cyclic GMP signaling and regulation of SERCA activity during cardiac myocyte contraction. Cell Calcium 37: 259–266, 2005.
 423. Zhang Y, Zhang GZ, Jiang N, Ma GD, Wen L, Bo H, Cao DN, Zhao F, SS L. A feedback molecular regulation of uncoupling and ROS generation in muscular mitochondria during an acute exercise. Chin J Sports Med 24: 389–394, 2005.
 424. Zhang YH, Zhang MH, Sears CE, Emanuel K, Redwood C, El‐Armouche A, Kranias EG, Casadei B. Reduced phospholamban phosphorylation is associated with impaired relaxation in left ventricular myocytes from neuronal NO synthase deficient mice. Circ Res 102: 242–249, 2008.
 425. Zhao X, Bey EA, Wientjes FB, Cathcart MK. Cytosolic phospholipase A2 (cPLA2) regulation of human monocyte NADPH oxidase activity. cPLA2 affects translocation but not phosphorylation of p67(phox) and p47(phox). J Biol Chem 277: 25385–25392, 2002.
 426. Zhou LZ, Johnson AP, Rando TA. NF kappa B and AP‐1 mediate transcriptional responses to oxidative stress in skeletal muscle cells. Free Radic Biol Med 31: 1405–1416, 2001.
 427. Zhou M, Lin BZ, Coughlin S, Vallega G, Pilch PF. UCP‐3 expression in skeletal muscle: Effects of exercise, hypoxia, and AMP‐activated protein kinase. Am J Physiol Endocrinol Metab 279: E622–E629, 2000.
 428. Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA. Treatment of symptomatic diabetic peripheral neuropathy with the anti‐oxidant alpha‐lipoic acid. A 3‐week multicentre randomized controlled trial (ALADIN Study). Diabetologia 38: 1425–1433, 1995.
 429. Zima AV, Blatter LA. Redox regulation of cardiac calcium channels and transporters. Cardiovasc Res 71: 310–321, 2006.
 430. Zissimopoulos S, Docrat N, Lai FA. Redox sensitivity of the ryanodine receptor interaction with FK506‐binding protein. J Biol Chem 282: 6976–6983, 2007.
 431. Zuo L, Christofi FL, Wright VP, Bao S, Clanton TL. Lipoxygenase‐dependent superoxide release in skeletal muscle. J Appl Physiol 97: 661–668, 2004.
 432. Zuo L, Christofi FL, Wright VP, Liu CY, Merola AJ, Berliner LJ, Clanton TL. Intra‐ and extracellular measurement of reactive oxygen species produced during heat stress in diaphragm muscle. Am J Physiol Cell Physiol 279: C1058–C1066, 2000.

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How to Cite

Scott K. Powers, Li Li Ji, Andreas N. Kavazis, Malcolm J. Jackson. Reactive Oxygen Species: Impact on Skeletal Muscle. Compr Physiol 2011, 1: 941-969. doi: 10.1002/cphy.c100054