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

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.

• Authors: Raquel Gómez-Oca, Evelina Edelweiss, Sarah Djeddi, Mathias Gerbier, Xènia Massana-Muñoz, Mustapha Oulad-Abdelghani, Corinne Crucifix, Coralie Spiegelhalter, Nadia Messaddeq, Pierre Poussin-Courmontagne, Pascale Koebel, Belinda S Cowling, Jocelyn Laporte
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 6849 (11 11 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 36369230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Dynamin II
• Protein Isoforms
• DNM2 protein, mouse

Topics

• Animals
• Mice
• Dynamin II (genetics)
• Muscle, Skeletal (pathology)
• Mutation
• Myopathies, Structural, Congenital (genetics, pathology)
• Phenotype
• Protein Isoforms (genetics)