The effect of N‐acetylcysteine on contractile function and protein‐thiol oxidation in skeletal muscles of mdx mice

Abstract

Duchenne Muscular Dystrophy (DMD) is a fatal X‐linked recessive disease characterized by severe muscle weakness. We hypothesized that oxidation of skeletal muscle proteins such as myosin contributes to dystrophic muscle weakness seen in DMD boys and dystrophic mdx mice and that this muscle weakness will be attenuated by treatment with the antioxidant N‐acetylcysteine (NAC).Six week old mdx mice and non‐dystrophic, C57 mice were treated with 2% NAC in drinking water for six weeks and compared to untreated mdx and C57 mice. Grip strength and body weight were measured weekly during the treatment period. After six weeks of treatment, the 12 week old mice were anaesthetized (sodium pentobarbitone; 40 mg/kg; IP) and the extensor digitorum longus (EDL) muscles were excised for analysis of contractile function and protein thiol‐oxidation.In mdx mice, NAC treatment significantly increased normalized grip strength and maximum specific force in isolated EDL muscles (NAC = 13.1 ± 1.2 N/cm2; Untreated = 9.8 ± 0.8 N/cm2, p<0.05), and significantly reduced myosin protein‐thiol oxidation (NAC = 10.6 ± 0.8 %; Untreated = 13.7 ± 0.8 %, p<0.05). In non‐dystrophic C57 mice, NAC treatment significantly increased normalized grip strength by 36%, but had no significant effect on maximum specific force or myosin protein‐thiol oxidation in EDL muscles.These data suggest that oxidative stress contributes to contractile dysfunction in dystrophic muscle via modification of thiol groups on the contractile protein myosin. Furthermore, this muscle weakness may be ameliorated with the anti‐oxidant, NAC.