Reactive oxygen species: impact on skeletal muscle

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.

Figure 1

Locations of the principal enzymatic and non-enzymatic antioxidants found in cells. Key to 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/prooxidant balance. Key to 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. Key to abbreviations: CAT = catalase; SOD1 = superoxide dismutase 1; SOD2 = superoxide dismutase 2; GPX = glutathione peroxidase.

Figure 4

A theoretical model proposed by Reid and colleagues (330) 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 Mike Reid (325).

Figure 5

Diagram of reputed redox sensitive targets in skeletal muscle that can impact muscle force production. Redrawn from Smith and Reid (375). Key to 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 (NF) κB; inducible nitric oxide synthase (iNOS), IL = interlurekin.