Olesoxime Does Not Affect Mitochondrial Dysfunction and Skeletal Muscle Pathology in Dystrophin-Deficient mdx Mice

Mitochondrial dysfunction is an important component in the pathogenesis of Duchenne muscular dystrophy (DMD). Although the mitochondrial voltage-dependent anion channel (VDAC) inhibitor olesoxime (TRO19622) has demonstrated efficacy in a severe DMD model, its effects in the classic mdx mouse model with a mild phenotype remain unclear. In this study, we administered olesoxime to 4-week-old mdx mice (20 mg/kg every other day for 4 weeks) and evaluated key parameters of mitochondrial function and muscle pathology. We found that olesoxime exerted no beneficial effects on impaired oxidative phosphorylation, calcium homeostasis, or mitochondrial ultrastructure; it also failed to reduce oxidative (4-HNE) or proteotoxic (calpain activity) stress levels, and did not improve muscle histopathology or functional indicators. These results demonstrate that, unlike in the severe DMD model, olesoxime does not exhibit therapeutic efficacy in the mdx mouse model. Our findings suggest that the effectiveness of mitochondron-targeted therapies based on VDAC inhibitors critically depends on the initial severity of mitochondrial dysfunction, which must be considered during the preclinical evaluation of potential therapeutic agents.