Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes.
Fiche publication
Date publication
août 2021
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Auteurs
Membres identifiés du Cancéropôle Est :
Mme MESSADDEQ Nadia
Tous les auteurs :
Silva-Rojas R, Nattarayan V, Jaque-Fernandez F, Gomez-Oca R, Menuet A, Reiss D, Goret M, Messaddeq N, Lionello VM, Kretz C, Cowling BS, Jacquemond V, Laporte J
Lien Pubmed
Résumé
Mutations in the BIN1 (Bridging Interactor 1) gene, encoding the membrane remodeling protein amphiphysin 2, cause centronuclear myopathy associated with severe muscle weakness and myofiber disorganization and hypotrophy. There is no available therapy, and the validation of therapeutic proof-of-concepts 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 centronuclear myopathy 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 targeting Dnm2 (Dynamin 2) that codes for dynamin 2, a BIN1 binding partner regulating membrane fission and mutated in other forms of centronuclear myopathy, improved muscle force and normalized the histological Bin1 phenotypes within 5 weeks. Overall, we generated a faithful mammalian model for centronuclear myopathy linked to BIN1 defects, and validated Dnm2 antisense oligonucleotides as a first translatable approach to efficiently treat BIN1-centronuclear myopathy.
Mots clés
amphiphysin, antisense oligonucleotides, dynamin, membrane curvature, myopathy, therapy
Référence
Mol Ther. 2021 Aug 6;: