Role of reactive oxygen species in the defective regeneration seen in aging muscle

Abstract

The ability of muscles to regenerate successfully following damage diminishes with age and this appears to be a major contributor to the development of muscle weakness and physical frailty. Successful muscle regeneration is dependent on appropriate reinnervation of regenerating muscle. Age-related changes in the interactions between nerve and muscle are poorly understood but may play a major role in the defective regeneration. During aging there is defective redox homeostasis and an accumulation of oxidative damage in nerve and muscle that may contribute to defective regeneration. The aim of this review is to summarise the evidence that abnormal reactive oxygen species (ROS) generation in nerve and/or muscle may be responsible for the defective regeneration that contributes to the degeneration of skeletal muscle observed during aging. Identifying the importance of ROS generation in skeletal muscle during aging could have fundamental implications for interventions to prevent muscle degeneration and treatments to reverse the age-related decline in muscle mass and function.

Keywords: AP-1; Aging; CNS; CuZnSOD; GPx1; GSH; HSPs; Innervation; MnSOD; NAD(P)H; NFκB; NMJs; NO; Neuromuscular junction; ROS; Reactive oxygen species; Regeneration; SOD; SOD1; Skeletal muscle; WT; XO; activator protein-1; central nervous system; copper, zinc superoxide dismutase; glutathione peroxidase 1; heat shock proteins; manganese superoxide dismutase; mpcs; myogenic precursor cells; nNOS; neuromuscular junctions; neuronal nitric oxide synthase; nitric oxide; nuclear transcription factor κappa B; reactive oxygen species; reduced glutathione; reduced nicotine adenine dinucleotide phosphate; superoxide dismutase; wild type; xanthine oxidase.

Fig. 1

Organization of a motor unit (a) Bundle of muscle fibers innervated by a motor neuron (b) Neuromuscular junction on a single muscle fiber (c) Fluorescent image of neuromuscular junctions and peripheral axons from the Tibialis Anterior (TA) muscle of a young thy1-YFP mouse. The underlying muscle fibers are stained with phalloidin.

Fig. 2

Muscle cell regeneration following damage. (A) Quiescent young muscle cell with peripheral nuclei and satellite cells. (B) Following damage, satellite cells are activated and start to proliferate. Satellite cells differentiation and fusion with (C) each other and (D) with the damaged muscle fiber. (E) Newly regenerated muscle fiber with central nuclei and renewed satellite cells. (F) Quiescent aged muscle cell with peripheral nuclei and satellite cells. (G) Following damage, satellite cells are activated to proliferate but proliferation is slower. Satellite cell differentiation and fusion with (H) each other and (I) with the damaged muscle fiber happens at a slower rate. (J) Incomplete regeneration of aged muscle fiber.

Fig. 3

Relative 3-nitrotyrosine content of carbonic anhydrase III in skeletal muscle of adult wild type, old wild type and adult Sod1^−/− mice (redrawn from [7]). Muscles of old wild type mice and adult mice lacking SOD1 have an elevated content of 3-nitrotyrosine residues in carbonic anhydrase III in comparison with muscles from adult wild type mice. Data are presented as a percentage of values from muscles of adult wild-type mice. *P<0.05 cf. adult wild type.