Differential impact of ubiquitous and muscle dynamin 2 isoforms in muscle physiology and centronuclear myopathy.
Fiche publication
Date publication
novembre 2022
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Mme MESSADDEQ Nadia , Dr OULAD-ABDELGHANI Mustapha , Mme KOEBEL Pascale
Tous les auteurs :
Gómez-Oca R, Edelweiss E, Djeddi S, Gerbier M, Massana-Muñoz X, Oulad-Abdelghani M, Crucifix C, Spiegelhalter C, Messaddeq N, Poussin-Courmontagne P, Koebel P, Cowling BS, Laporte J
Lien Pubmed
Résumé
Dynamin 2 mechanoenzyme is a key regulator of membrane remodeling and gain-of-function mutations in its gene cause centronuclear myopathies. Here, we investigate the functions of dynamin 2 isoforms and their associated phenotypes and, specifically, the ubiquitous and muscle-specific dynamin 2 isoforms expressed in skeletal muscle. In cell-based assays, we show that a centronuclear myopathy-related mutation in the ubiquitous but not the muscle-specific dynamin 2 isoform causes increased membrane fission. In vivo, overexpressing the ubiquitous dynamin 2 isoform correlates with severe forms of centronuclear myopathy, while overexpressing the muscle-specific isoform leads to hallmarks seen in milder cases of the disease. Previous mouse studies suggested that reduction of the total dynamin 2 pool could be therapeutic for centronuclear myopathies. Here, dynamin 2 splice switching from muscle-specific to ubiquitous dynamin 2 aggravated the phenotype of a severe X-linked form of centronuclear myopathy caused by loss-of-function of the MTM1 phosphatase, supporting the importance of targeting the ubiquitous isoform for efficient therapy in muscle. Our results highlight that the ubiquitous and not the muscle-specific dynamin 2 isoform is the main modifier contributing to centronuclear myopathy pathology.
Mots clés
Animals, Mice, Dynamin II, genetics, Myopathies, Structural, Congenital, genetics, Muscle, Skeletal, pathology, Phenotype, Mutation, Protein Isoforms, genetics
Référence
Nat Commun. 2022 11 11;13(1):6849