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INVITED EDITORIAL
Service d'Explorations Fonctionnelles Cardio-Vasculaires et Respiratoires, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France
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., <10 thiols) has little effect on SR Ca2+ release channel activity, whereas moderate level of oxidation (i.e., 
20–30 thiols) increases channel activity, and extensive 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-
(PPAR), a member of the superfamily of lipid-activated nuclear receptors. PPAR 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 PPAR null mice exhibit major oxidative stress damage localized on the myosin head, leading to cardiac dysfunction (6). PPAR 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, PPAR, 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).
FOOTNOTES
Address 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: lecarpentier.y{at}wanadoo.fr)
REFERENCES
–/– mice. Am J Physiol Heart Circ Physiol 293: H93–H102, 2007.: essential component to prevent myocardial oxidative stress? Am J Physiol Heart Circ Physiol 293: H11–H12, 2007.
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