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

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 () and Jocelyn Laporte ()
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Raquel Gómez-Oca: Université de Strasbourg
Evelina Edelweiss: Université de Strasbourg
Sarah Djeddi: Université de Strasbourg
Mathias Gerbier: Dynacure
Xènia Massana-Muñoz: Université de Strasbourg
Mustapha Oulad-Abdelghani: Université de Strasbourg
Corinne Crucifix: Université de Strasbourg
Coralie Spiegelhalter: Université de Strasbourg
Nadia Messaddeq: Université de Strasbourg
Pierre Poussin-Courmontagne: Université de Strasbourg
Pascale Koebel: Université de Strasbourg
Belinda S. Cowling: Dynacure
Jocelyn Laporte: Université de Strasbourg

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34490-4

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DOI: 10.1038/s41467-022-34490-4

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