2026-04-26T23:12:46Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/261382025-12-18T12:52:26Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Silva-Rojas, Roberto author Nattarayan, Vasugi author Jaque-Fernandez, Francisco author Gomez-Oca, Raquel author Menuet, Alexia author Reiss, David author Goret, Marie author Messaddeq, Nadia author Lionello, Valentina M author Kretz, Christine author Cowling, Belinda S author Jacquemond, Vincent author Laporte, Jocelyn author 2022-02-02 Mutations in the BIN1 (Bridging Interactor 1) gene, encoding the membrane remodeling protein amphiphysin 2, cause centronuclear myopathy (CNM) associated with severe muscle weakness and myofiber disorganization and hypotrophy. There is no available therapy, and the validation of therapeutic proof of concept is impaired by the lack of a faithful and easy-to-handle mammalian model. Here, we generated and characterized the Bin1 mouse through Bin1 knockout in skeletal muscle. Bin1 mice were viable, unlike the constitutive Bin1 knockout, and displayed decreased muscle force and most histological hallmarks of CNM, including myofiber hypotrophy and intracellular disorganization. Notably, Bin1 myofibers presented strong defects in mitochondria and T-tubule networks associated with deficient calcium homeostasis and excitation-contraction coupling at the triads, potentially representing the main pathomechanisms. Systemic injection of antisense oligonucleotides (ASOs) targeting Dnm2 (Dynamin 2), which codes for dynamin 2, a BIN1 binding partner regulating membrane fission and mutated in other forms of CNM, improved muscle force and normalized the histological Bin1 phenotypes within 5 weeks. Overall, we generated a faithful mammalian model for CNM linked to BIN1 defects and validated Dnm2 ASOs as a first translatable approach to efficiently treat BIN1-CNM. Mol Ther. 2022 Feb 2;30(2):868-880. https://hdl.handle.net/20.500.12105/26138 34371181 Molecular Therapy MTM1 amphiphysin antisense oligonucleotides dynamin membrane curvature myopathy myotubular myopathy myotubularin t-tubule therapy Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes.