Generation of reactive oxygen and nitrogen species in contracting skeletal muscle: Potential impact on aging

Since the early 1980s biologists have recognized that skeletal muscle generates free radicals. Of particular interest are two closely related redox cascades-reactive oxygen species (RES) and nitric oxide (NO) derivatives. The Res cascade is initiated by superoxide anion radicals derived from the mitochondrial electron transport chain, the membrane-associated NAD(P)H oxidase complex, or other sources. NO is produced by two NO synthase isoforms constitutively expressed by muscle fibers. Res and NO derivatives are produced continually and are detectable in both the cytosolic and extracellular compartments. Production increases during strenuous exercise. Both Res and NO modulate contractile function. Under basal conditions, low levels of ROS enhance force production. Excessive Res accumulation inhibits force, for example, during fatiguing exercise. NO inhibits skeletal muscle contraction, an effect that is partially mediated by cyclic GMP as a second messenger. With aging, redox modulation of muscle contraction may be altered by changes in the rates of ROS and NO production, the levels of endogenous antioxidants that buffer ROS and NO, and the sensitivities of regulatory proteins to ROS and NO action. The impact of aging on contractile regulation depends on the relative magnitude of these changes and their net effects on ROS and NO activities at the cellular level.