BIN1 overexpression rescues cardiac but not skeletal muscle defects in a mouse model of caveolinopathy

Mutations in CAV3, encoding caveolin-3, cause caveolinopathies, rare genetic disorders affecting both skeletal and cardiac muscle. Caveolin-3 contributes to T-tubule formation and excitation-contraction coupling. To date, there are no therapy for caveolinopathies. BIN1 (amphiphysin 2), a membrane-shaping protein critical for T-tubule integrity, has shown therapeutic promise in congenital myopathies and heart dysfunction. We evaluated the therapeutic impact of BIN1 overexpression in Cav-3 knockout mice, a model recapitulating key features of human caveolinopathy. We assessed skeletal and cardiac function, T-tubule morphology, mitochondria, and gene expression using histological, physiological, and molecular approaches. Results: We found Cav-3-/- mice displayed skeletal muscle weakness, T-tubule disorganization, and mitochondrial abnormalities, alongside cardiac diastolic dysfunction and myofibrillar disarray. While BIN1 overexpression failed to improve muscle strength, T-tubule structure, or fiber atrophy, it corrected nuclear positioning and partially restored mitochondrial markers in skeletal muscle. In contrast, BIN1 robustly rescued cardiac performance, restoring end-diastolic volume, cardiac output, and sarcomeric integrity. Expression profiling revealed greater dysregulation of excitation-contraction coupling and atrogene pathways in skeletal than in cardiac muscle in Cav-3-/- mice. Cavin-4, a BIN1-interacting protein and caveolar component, was selectively dysregulated in Cav-3-/- muscle, suggesting a mechanistic barrier to BIN1-mediated rescue in this tissue. These findings identify tissue-specific differences in the molecular consequences of caveolin-3 loss and demonstrate that BIN1 overexpression effectively rescues cardiac manifestations of caveolinopathy while only partially ameliorating the associated subcellular defects in skeletal muscle. Our results support BIN1 investigation as a potential target for inherited cardiomyopathies, while highlighting the need for alternative strategies in skeletal muscle.