Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production

Abstract

The first suggestion that physical exercise results in free radical-mediated damage to tissues appeared in 1978, and the past three decades have resulted in a large growth of knowledge regarding exercise and oxidative stress. Although the sources of oxidant production during exercise continue to be debated, it is now well established that both resting and contracting skeletal muscles produce reactive oxygen species and reactive nitrogen species. Importantly, intense and prolonged exercise can result in oxidative damage to both proteins and lipids in the contracting myocytes. Furthermore, oxidants can modulate a number of cell signaling pathways and regulate the expression of multiple genes in eukaryotic cells. 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, DNA repair 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 promote contractile dysfunction resulting in muscle weakness and fatigue. Ongoing research continues to probe the mechanisms by which oxidants influence skeletal muscle contractile properties and to explore interventions capable of protecting muscle from oxidant-mediated dysfunction.

FIG. 1

Arachidonic acid undergoing initiation and propagation stages of lipid peroxidation. MDA, malondialdehyde. [Adapted from Halliwell and Gutteridge (136).]

FIG. 2

Locations of primary cellular enzymatic and nonenzymatic antioxidants. GPX, glutathione peroxidase; SOD1, superoxide dismutase 1; SOD2, superoxide dismutase 2.

FIG. 3

The four broad classes of biomarkers used to assess cellular oxidative stress in tissues. These categories include the measurement of oxidant production, cellular levels of antioxidants, oxidation products, and the antioxidant/pro-oxidant balance. 8-OH-dG, 8-hydroxydeoxyguanosine; GSH/GSSG, ratio of reduced glutathione to oxidized glutathione.

FIG. 4

Potential sites for the production of superoxide and nitric oxide in skeletal muscle.

FIG. 5

A theoretical model proposed by Reid et al. (322) 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. [Redrawn from Reid (317).]

FIG. 6

Illustration of putative redox-sensitive targets in skeletal muscle that can influence force production. SOD, superoxide dismutase; NOS, nitric oxide synthase; NO, nitric oxide; SERCA, sarcoplasmic reticulum calcium ATPase. [Redrawn from Smith and Reid (368).]

FIG. 7

Hypothetical model depicting muscle responses to increasing oxidation of redox-sensitive components due to increased ROS exposure. It is envisaged that a low-level increase in ROS exposure changes the cellular redox state to initially affect redox-sensitive signaling pathways and if sufficiently large or sustained may lead to cellular damage (middle panel). It seems likely that it will not be possible to clearly demarcate the amounts of oxidation required to invoke differing responses, and hence, the boundaries between these actions are not shown as solid lines. Where in this spectrum of events traditional marker of ROS activity, such as measures of lipid, DNA, or protein oxidation, become abnormal is currently unknown (and hence these are also demarcated by dotted lines in left panel). Contractile activity is known to lead to an increase in ROS generation in muscle, but the factors that govern when this is sufficient to change the redox status and activate redox-sensitive signaling event or lead to damage are not understood (right panel). Possible factors influencing the magnitude of this response include the nature and duration of the contractile activity, the antioxidant status of the muscle, and the basal redox status prior to exercise.