Differential impact of ubiquitous and muscle dynamin 2 isoforms in muscle physiology and centronuclear myopathy

Raquel Gomez Oca (1) , Evelina Edelweiss (1) , Sarah Djeddi (1) , Mathias Gerbier , Xènia Massana Munoz (1) , Mustapha Oulad-Abdelghani (1) , Corinne Crucifix (1) , Coralie Spiegelhalter (1) , Nadia Messaddeq (1) , Pierre Poussin-Courmontagne (1) , Pascale Koebel (1) , Belinda Cowling (1) , Jocelyn Laporte (1)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

Abstract 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.

Domaines: Biochimie, Biologie Moléculaire

Raquel Gomez Oca, Evelina Edelweiss, Sarah Djeddi, Mathias Gerbier, Xènia Massana Munoz, et al.. Differential impact of ubiquitous and muscle dynamin 2 isoforms in muscle physiology and centronuclear myopathy. Nature Communications, 2022, 13 (1), ⟨10.1038/s41467-022-34490-4⟩. ⟨hal-04076609⟩