Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1Y522S/WTMice

Abstract

Central core disease (CCD) is a congenital myopathy linked to mutations in the ryanodine receptor type 1 (RYR1), the sarcoplasmic reticulum Ca2+release channel of skeletal muscle. CCD is characterized by formation of amorphouscoreswithin muscle fibers, lacking mitochondrial activity. In skeletal muscle of RYR1Y522S/WTknock-in mice, carrying a human mutation in RYR1 linked to malignant hyperthermia (MH) withcores, oxidative stress is elevated and fibers present severe mitochondrial damage andcores. We treated RYR1Y522S/WTmice with N-acetylcysteine (NAC), an antioxidant providedad libitumin 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 ofunstructuredandcontracture cores, (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 ofcoresand improve muscle function in RYR1Y522S/WTmice.