VBIT-4 Rescues Mitochondrial Dysfunction and Reduces Skeletal Muscle Degeneration in a Severe Model of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the gene, leading to progressive muscle degeneration and fibrosis. A key pathological feature of DMD is mitochondrial dysfunction driven by calcium overload, which disrupts oxidative phosphorylation and triggers cell death pathways. This study shows the therapeutic potential of VBIT-4, a novel inhibitor of the mitochondrial voltage-dependent anion channel (VDAC), in two dystrophin-deficient mouse models: the mild and the severe D2.DMDel8-34 strains. VBIT-4 administration (20 mg/kg) reduced mitochondrial calcium overload, enhanced resistance to permeability transition pore induction, and improved mitochondrial ultrastructure in D2.DMDel8-34 mice, while showing negligible effects in mice. VBIT-4 suppressed mitochondrial and total calpain activity and reduced endoplasmic reticulum stress markers, suggesting a role in mitigating proteotoxic stress. However, it did not restore oxidative phosphorylation or reduce oxidative stress. Functional assays revealed limited improvements in muscle strength and fibrosis reduction, exclusively in the severe model. These findings underscore VDAC as a promising target for severe DMD and highlight the critical role of mitochondrial calcium homeostasis in DMD progression.