Effects of N-acetyl-L-cysteine and vitamin E on congenital muscular dystrophy type 1A disease progression in mice

Congenital muscular dystrophy with laminin alpha2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without cure. Previously, we have demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models using transcriptome and proteome profiling as well and functional assays (e.g. reduced mitochondrial respiration and a compensatory upregulation of glycolysis). Reactive oxygen species (ROS) form naturally during normal metabolism of oxygen but increase when oxygen homeostasis is not maintained. Here we demonstrate that ROS levels are indeed increased in LAMA-CMD mouse muscle. Next, we investigated the effects of the antioxidant N-acetyl-L-cysteine (NAC) and vitamin E, respectively, in reducing disease progression in the dy2J/dy2J mouse model of LAMA2-CMD. NAC treatment (150 mg/kg, IP six times a week for three weeks) enhanced muscle strength, reduced central nucleation, apoptosis, inflammation and fibrosis and decreased oxidative stress in LAMA2-CMD muscle. In addition, vitamin E (40 mg/kg, oral gavage six times a week for two weeks) improved morphological features and reduced inflammation and ROS levels in dy2J/dy2J muscle. Neither NAC nor vitamin E targets the primary genetic defect and is not expected to completely cure LAMA2-CMD. However, we suggest that NAC and to some extent vitamin E might be potential future supportive treatments for LAMA2-CMD as they improve numerous pathological hallmarks of LAMA2-CMD. Both NAC and vitamin E are already approved for use in humans, which is beneficial from a clinical point of view