Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1 Mice.

Central core disease (CCD) is a congenital myopathy linked to mutations in the ryanodine receptor type 1 (RYR1), the sarcoplasmic reticulum Ca release channel of skeletal muscle. CCD is characterized by formation of amorphous within muscle fibers, lacking mitochondrial activity. In skeletal muscle of RYR1 knock-in mice, carrying a human mutation in RYR1 linked to malignant hyperthermia (MH) with , oxidative stress is elevated and fibers present severe mitochondrial damage and . We treated RYR1 mice with N-acetylcysteine (NAC), an antioxidant provided in drinking water for either 2 or 6 months. Our results show that 2 months of NAC treatment starting at 2 months of age, when mitochondrial and fiber damage was still minimal, (i) reduce formation of and , (ii) improve muscle function, and (iii) decrease mitochondrial damage. The beneficial effect of NAC treatment is also evident following 6 months of treatment starting at 4 months of age, when structural damage was at an advanced stage. NAC exerts its protective effect likely by lowering oxidative stress, as supported by the reduction of 3-NT and SOD2 levels. This work suggests that NAC administration is beneficial to prevent mitochondrial damage and formation of and improve muscle function in RYR1 mice.