BIN1 overexpression rescues cardiac but not skeletal muscle defects in a mouse model of caveolinopathy
Abstract
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.
Related
- EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions
- Mdfi overexpression promotes oxidative muscle fiber formation without affecting muscle development in mature skeletal muscles.
- Rapsyn overexpression improves neuromuscular junction and skeletal muscle function after tourniquet-induced mouse hindlimb ischemia-reperfusion injuries
- Protein inhibitor of retinal membrane guanylyl cyclase rescues photoreceptors from degeneration induced by mutated guanylyl cyclase activating protein
- A second-generation “hypoxia in a pill” rescues neurodegenerative phenotypes across distinct mouse models
BibTeX
@misc{moncheaux2026bin1,
title = {{BIN1 overexpression rescues cardiac but not skeletal muscle defects in a mouse model of caveolinopathy}},
author = {Alice Moncheaux and Alain Guimond and Coralie Spiegelhalter and Nadia Messaddeq and Chadia Nahy and Jocelyn Laporte},
howpublished = {Human Molecular Genetics},
year = {2026},
month = aug,
doi = {10.1101/2025.09.26.678914},
url = {https://univoak.hal.science/hal-05751685v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - BIN1 overexpression rescues cardiac but not skeletal muscle defects in a mouse model of caveolinopathy
AU - Alice Moncheaux
AU - Alain Guimond
AU - Coralie Spiegelhalter
AU - Nadia Messaddeq
AU - Chadia Nahy
AU - Jocelyn Laporte
PY - 2026
DA - 2026/08/25
PB - Human Molecular Genetics
DO - 10.1101/2025.09.26.678914
UR - https://univoak.hal.science/hal-05751685v1
AB - 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.
SN - 0964-6906
SN - 1460-2083
ER -