Physiological role of free radicals in skeletal muscles
2007; American Physiological Society; Volume: 103; Issue: 6 Linguagem: Inglês
10.1152/japplphysiol.01047.2007
ISSN8750-7587
Autores Tópico(s)Coenzyme Q10 studies and effects
ResumoINVITED EDITORIALPhysiological role of free radicals in skeletal musclesYves LecarpentierYves LecarpentierPublished Online:01 Dec 2007https://doi.org/10.1152/japplphysiol.01047.2007This is the final version - click for previous versionMoreSectionsPDF (42 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat for a long time, "oxidative stress" induced by both reactive oxygen species (ROS) and reactive nitrogen species (RNS) has been shown to be associated with chronic pathological events. Indeed, free radicals are often considered as markers of cellular injury or death, making mischief in a large cohort of chronic illnesses such as cancer, diabetes mellitus, atherosclerosis, heart failure, ischemia and reperfusion injury, neurodegenerative diseases, rheumatoid arthritis, and HIV infection, to name a few. Cellular damage appearing during aging may also be partly attributed to free radical species.At relatively low cellular levels, however, free radicals may influence metabolism in physiological conditions. Reactive oxygen and nitrogen species are involved in the maintenance of "redox homeostasis." Redox signaling describes regulatory processes in which the signal is delivered through redox cellular chemistry (5). Changes in the oxidant-antioxidant balance act as a trigger for redox homeostasis. After a temporary increase in cellular ROS or RNS concentrations, the initial redox state can be reestablished by numerous compensatory mechanisms. For example, 1) an increase in ROS may induce expression of certain genes exhibiting antioxidative activity; and 2) nitric oxide (NO) production induces a direct feedback inhibition of NO synthase by NO. In a physiological range, the antioxidative response to a moderate increase in ROS may be sufficient to reset the balance between ROS production and ROS-scavenging capacity. Thus redox homeostasis can be maintained in a near-equilibrium stationary thermodynamic state (10, 11) or quasi-stable state (5). When the redox system is subjected to dramatic and/or long-lasting perturbations, it may behave in a manner that is far from equilibrium, where instability and thermodynamic bifurcations toward chronic pathological states may appear (10).From a historical point of view, skeletal muscles have been known to generate free radical intermediates since the 1950s (3). Production of ROS and RNS associated with muscular exercise appeared only in the 1970s. However, the paradigm that free radicals, constitutive elements of the physiological milieu, may play a true physiological role in skeletal muscle function was introduced by M. Reid, a pioneer in this field (14, 15). Reid and colleagues showed that diaphragm muscle fibers released superoxide anion radicals (15). Moreover, exogenous hydrogen peroxide increased peak twitch tension in fiber bundles from rat diaphragm, although exogenous catalase, an antioxidant enzyme that dehydrates hydrogen peroxide to molecular oxygen and water, decreased peak twitch tension (14). Thus free radical species could physiologically modulate diaphragm muscle performance. ROS and RNS production by skeletal muscles and redox modulation of skeletal muscle contractility have been reviewed (8, 13, 18). Generation of free radicals by skeletal muscles is potentially important if we consider that they represent the largest organ in the human body.In the model proposed by Reid (13), the ROS-induced effects on muscle inotropy depend on ROS concentrations and degree of muscle fatigue. In unfatigued skeletal muscle, ROS induce a biphasic effect on the contractile function. Indeed, the low ROS levels present under basal contractile conditions are necessary to preserve normal muscle performance. A moderate increase in ROS induces an increase in force development. However, at higher ROS concentrations, this positive inotropic effect is reversed. The negative inotropic effects obtained at high ROS concentrations can be prevented by antioxidant pretreatment and reversed by antioxidant agents. Conversely, during strenuous exercise, ROS are generated faster than the buffering capacity provided by endogenous antioxidants, so that muscle performance is impaired. In fatigued muscle, pretreatment by antioxidants can also blunt the negative inotropic ROS effects. This model depicts a balance between physiological free radical generation and antioxidant buffering capabilities. In short, the cytosolic redox state presents an optimum, and any deviation from this optimum induces a loss in muscle performance. This redox optimum corresponds to a state where muscle is exposed to low levels of ROS.In a study in the Journal of Applied Physiology, Tupling and coworkers (22) present an interesting and elegant study in which isolated diaphragm contractility and the function of the sarcoplasmic reticulum Ca2+ pump (SERCA) were tested in rats after treatment by buthionine sulfoximine (BSO; 20 mM in drinking water for 10 days). BSO depletes cellular glutathione (GSH) and consequently reduces antioxidant defenses. GSH is a nonenzymatic cellular antioxidant that acts as an electron donor for the glutathione peroxidase (GPX) reaction: H2O2 + 2GSH ⇄ 2H2O + GSSG. Hydrogen peroxide (H2O2) is provided by the enzymatic action of the superoxide dismutase on the superoxide anion. Moreover, GSH induces direct antioxidant effects.In the study of Tupling et al. (22), BSO treatment resulted in an increase in peak twitch force and exacerbated muscle fatigue. These results corroborate those obtained by Reid and coworkers (14, 15), where exogenous hydrogen peroxide increased peak twitch tension in fiber bundles from rat diaphragm, although exogenous catalase, an antioxidant enzyme that dehydrates hydrogen peroxide to molecular oxygen and water, decreased peak twitch tension. Furthermore, Tupling and coworkers also examined the effects of glutathione depletion on the sarcoplasmic reticulum (SR) function. In control conditions, SERCA2a expression was shown to be increased with BSO treatment. However, during muscle fatigue, SR Ca2+ uptake and maximal SERCA activity measured in homogenates were improved in BSO-untreated diaphragm but not in BSO-treated diaphragm. Thus fatigue modified the SR function of treated and untreated diaphragm muscles in a different manner. Tupling's results strongly suggest that free radical species play a physiological role in the SR function and also induce a biphasic effect as previously shown by Reid and coworkers (13–15). These results reinforce previous data showing that the Ca2+ release channel/ryanodine receptor (RyR1) responds to moderate oxidative stress by a change in activation set point, although the channel is susceptible to oxidative injury under more extensive conditions (17). SR Ca2+ release channel contains a large number of free thiols. Low level of oxidation (i.e., 35 thiols) inactivates the channel irreversibly. However, the lusitropic mechanical properties of diaphragm strips have not been investigated. A study of the mechanical properties of relaxation over the entire range of loading conditions may be potentially interesting if one wants to examine the SR function. Like the heart, the diaphragm contracts rhythmically throughout life and must return to a relatively constant resting position at the end of the relaxation phase. In all sarcomeric mammalian muscles, relaxation has been shown to be sensitive to loading conditions (1). This mechanical property requires a well-functioning SR. In diaphragm muscle, both fatigue and ryanodine, a specific inhibitor of the SR, impair the load sensitivity of relaxation due to dysfunction of the SR (7). If free radicals modulate the SR function, it may be inferred that load sensitivity of relaxation could also be modified by free radical species. Such a hypothesis warrants further study.ATP synthesis allowing cyclic acto-myosin interactions results from glucose and fatty acid metabolism. Therefore, it may be important to analyze the potential links between muscle metabolism during contraction and production of ROS. Modulation of glucose transport in skeletal muscle by ROS has recently been reviewed (9). Pharmacological and genetic studies support a role for ROS in contraction-mediated glucose transport via AMP-activated protein kinase. An optimal ROS production is required for normal activation of contraction-mediated glucose transport, also suggesting a biphasic effect induced by free radical species. Excessive exogenous antioxidants can have deleterious effects on glucose utilization during contraction. In addition, a link has recently been identified between production of ROS and peroxisome proliferator-activated receptor-α (PPARα), a member of the superfamily of lipid-activated nuclear receptors. PPARα is expressed at relatively high levels in cardiac and skeletal muscles and activates numerous genes involved in cellular fatty acid uptake and β-oxidation (4). It has been shown that PPARα null mice exhibit major oxidative stress damage localized on the myosin head, leading to cardiac dysfunction (6). PPARα may emerge as a new component to prevent myocardial stress (16). A similar effect on skeletal muscle remains to be demonstrated.Thus free radical species seem to play an important role in redox homeostasis by modulating several major regulatory systems of skeletal muscle performance such as mitochondria, sarcoplasmic reticulum, glucose transport, PPARα, and numerous other enzymatic systems involved in the cellular metabolism. A weak production of free radical species is necessary for normal contractile activity of skeletal muscles (13). If moderate and temporary fluctuations of free radical concentrations remain within a physiological range, the redox homeostasis of skeletal muscles is maintained in a stationary thermodynamic state (5). On the contrary, cellular regulatory systems of redox homeostasis can be overwhelmed, resulting possibly in far from equilibrium thermodynamic behavior (10) and muscle dysfunction (18, 19). States in which high levels of free radical species are produced in muscles may occur in various pathological processes such as hypoxia (2), inflammation (20, 23), muscular dystrophy (21), and disuse muscle atrophy (12).REFERENCES1 Brutsaert DL, Housmans PR, Goethals MA. Dual control of relaxation. Its role in the ventricular function in the mammalian heart. Circ Res 47: 637–652, 1980.Crossref | PubMed | ISI | Google Scholar2 Clanton TL. Hypoxia-induced reactive oxygen species formation in skeletal muscle. J Appl Physiol 102: 2379–2388, 2007.Link | ISI | Google Scholar3 Commoner B, Townsend J, Pake GE. Free radicals in biological materials. Nature 174: 689–691, 1954.Crossref | PubMed | ISI | Google Scholar4 Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20: 649–688, 1999.Crossref | PubMed | ISI | Google Scholar5 Droge W. Free radicals in the physiological control of cell function. Physiol Rev 82: 47–95, 2002.Link | ISI | Google Scholar6 Guellich A, Damy T, Lecarpentier Y, Conti M, Claes V, Samuel JL, Quillard J, Hebert JL, Pineau T, Coirault C. Role of oxidative stress in cardiac dysfunction of PPARα−/− mice. Am J Physiol Heart Circ Physiol 293: H93–H102, 2007.Link | ISI | Google Scholar7 Herve P, Lecarpentier Y, Brenot F, Clergue M, Chemla D, Duroux P. Relaxation of the diaphragm muscle: influence of ryanodine and fatigue. J Appl Physiol 65: 1950–1956, 1988.Link | ISI | Google Scholar8 Jackson MJ, Pye D, Palomero J. The production of reactive oxygen and nitrogen species by skeletal muscle. J Appl Physiol 102: 1664–1670, 2007.Link | ISI | Google Scholar9 Katz A. Modulation of glucose transport in skeletal muscle by reactive oxygen species. J Appl Physiol 102: 1671–1676, 2007.Link | ISI | Google Scholar10 Kondepudi D, Prigogine I. Modern Thermodynamics from Heat Engines to Dissipative Structures. New York: Wiley, 1999.Google Scholar11 Lecarpentier Y, Blanc FX, Quillard J, Hebert JL, Krokidis X, Coirault C. Statistical mechanics of myosin molecular motors in skeletal muscles. J Theor Biol 235: 381–392, 2005.Crossref | ISI | Google Scholar12 Powers SK, Kavazis AN, McClung JM. Oxidative stress and disuse muscle atrophy. J Appl Physiol 102: 2389–2397, 2007.Link | ISI | Google Scholar13 Reid MB. Redox modulation of skeletal muscle contraction: what we know and what we don't. J Appl Physiol 90: 724–731, 2001.Link | ISI | Google Scholar14 Reid MB, Khawli FA, Moody MR. Reactive oxygen in skeletal muscle. III. Contractility of unfatigued muscle. J Appl Physiol 75: 1081–1087, 1993.Link | ISI | Google Scholar15 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.Link | ISI | Google Scholar16 Schulz R, Ali MA. PPARα: essential component to prevent myocardial oxidative stress? Am J Physiol Heart Circ Physiol 293: H11–H12, 2007.Link | ISI | Google Scholar17 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.Crossref | PubMed | ISI | Google Scholar18 Supinski G. Free radical induced respiratory muscle dysfunction. Mol Cell Biochem 179: 99–110, 1998.Crossref | PubMed | ISI | Google Scholar19 Supinski G, Nethery D, Stofan D, DiMarco A. Extracellular calcium modulates generation of reactive oxygen species by the contracting diaphragm. J Appl Physiol 87: 2177–2185, 1999.Link | ISI | Google Scholar20 Supinski GS, Callahan LA. Free radical-mediated skeletal muscle dysfunction in inflammatory conditions. J Appl Physiol 102: 2056–2063, 2007.Link | ISI | Google Scholar21 Tidball JG, Wehling-Henricks M. The role of free radicals in the pathophysiology of muscular dystrophy. J Appl Physiol 102: 1677–1686, 2007.Link | ISI | Google Scholar22 Tupling AR, Vigna C, Ford RJ, Tsuchiya SC, Graham DA, Denniss SG, Rush JWE. Effects of buthionine sulfoximine treatment on diaphragm contractility and SR Ca2+ pump function in rats. J Appl Physiol (August 23, 2007). doi:10.1152/japplphysiol.00529.2007.Google Scholar23 Vassilakopoulos T, Hussain SN. Ventilatory muscle activation and inflammation: cytokines, reactive oxygen species, and nitric oxide. J Appl Physiol 102: 1687–1695, 2007.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: Y. Lecarpentier, Service d'Explorations Fonctionnelles Cardio-Vasculaires et Respiratoires, Hôpital de Bicêtre, 78 Ave. du Général Leclerc, 94275 Le Kremlin-Bicêtre, France (e-mail: [email protected]) Download PDF Back to Top Next FiguresReferencesRelatedInformationCited ByPGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice4 November 2019 | Acta Physiologica, Vol. 228, No. 4Endospanin-2 enhances skeletal muscle energy metabolism and running endurance capacity3 May 2018 | JCI Insight, Vol. 3, No. 9Effects of wheat peptide supplementation on anti-fatigue and immunoregulation during incremental swimming exercise in rats1 January 2017 | RSC Advances, Vol. 7, No. 69Reversible oxidation of vicinal-thiols motif in sarcoplasmic reticulum calcium regulatory proteins is involved in muscle fatigue mechanismCell Calcium, Vol. 60, No. 4Ação do licopeno nos músculos esquelético e cardíaco sob estresse oxidativo por exercíciosRevista Brasileira de Medicina do Esporte, Vol. 20, No. 2Dual Oxidase Maturation factor 1 (DUOXA1) overexpression increases reactive oxygen species production and inhibits murine muscle satellite cell differentiationCell Communication and Signaling, Vol. 12, No. 1The Influence of Erythropoietin (EPO T → G) and a-Actinin-3 (ACTN3 R577X) Polymorphisms on Runners' Responses to the Dietary Ingestion of Antioxidant Supplementation Based on Pequi Oil ( Caryocar brasiliense Camb.): A Before-After StudyJournal of Nutrigenetics and Nutrigenomics, Vol. 6, No. 6Local Injections of Adipose-Derived Mesenchymal Stem Cells Modulate Inflammation and Increase Angiogenesis Ameliorating the Dystrophic Phenotype in Dystrophin-Deficient Skeletal Muscle27 August 2011 | Stem Cell Reviews and Reports, Vol. 8, No. 2Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-120 July 2011 | European Heart Journal, Vol. 33, No. 11Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-κB inhibitor (IκB)–nuclear factor-κB (NFκB) activation in rat muscle, in the absence of mitochondrial dysfunction13 December 2011 | Diabetologia, Vol. 55, No. 3Does Branched-Chain Amino Acids Supplementation Modulate Skeletal Muscle Remodeling through Inflammation Modulation? Possible Mechanisms of ActionJournal of Nutrition and Metabolism, Vol. 2012Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stressJamal Bouitbir, Anne-Laure Charles, Laurence Rasseneur, Stéphane Dufour, François Piquard, Bernard Geny, and Joffrey Zoll1 November 2011 | Journal of Applied Physiology, Vol. 111, No. 5Genetic polymorphisms influence runners' responses to the dietary ingestion of antioxidant supplementation based on pequi oil (Caryocar brasiliense Camb.): a before-after study11 April 2011 | Genes & Nutrition, Vol. 6, No. 4Increased oxidative stress in dystrophin deficient (mdx) mice masticatory musclesExperimental and Toxicologic Pathology, Vol. 63, No. 6PPARs, Cardiovascular Metabolism, and Function: Near- or Far-from-Equilibrium PathwaysPPAR Research, Vol. 2010Evaluation of gene polymorphisms in exercise-induced oxidative stress and damage29 January 2010 | Free Radical Research, Vol. 44, No. 3Pequi fruit (Caryocar brasiliense Camb.) pulp oil reduces exercise-induced inflammatory markers and blood pressure of male and female runnersNutrition Research, Vol. 29, No. 12Ectopic Catalase Expression in Mitochondria by Adeno-Associated Virus Enhances Exercise Performance in Mice19 August 2009 | PLoS ONE, Vol. 4, No. 8Mitochondrial Reactive Oxygen Species Production in Excitable Cells: Modulators of Mitochondrial and Cell FunctionAntioxidants & Redox Signaling, Vol. 11, No. 6The decay phase of Ca 2+ transients in skeletal muscle: regulation and physiologyThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal's usual peer review process.Applied Physiology, Nutrition, and Metabolism, Vol. 34, No. 3 More from this issue > Volume 103Issue 6December 2007Pages 1917-1918 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01047.2007PubMed17916668History Published online 1 December 2007 Published in print 1 December 2007 Metrics
Referência(s)