MTM1 overexpression prevents and reverts BIN1-related centronuclear myopathy - Archive ouverte HAL
Journal Articles Brain - A Journal of Neurology Year : 2023

MTM1 overexpression prevents and reverts BIN1-related centronuclear myopathy

Abstract

Centronuclear and myotubular myopathies (CNM) are rare and severe genetic diseases associated with muscle weakness and atrophy as well as intracellular disorganization of myofibres. The main mutated proteins control lipid and membrane dynamics and are the lipid phosphatase myotubularin (MTM1), and the membrane remodelling proteins amphiphysin 2 (BIN1) and dynamin 2 (DNM2). There is no available therapy. Here, to validate a novel therapeutic strategy for BIN1- and DNM2-CNM, we evaluated adeno-associated virus-mediated MTM1 (AAV-MTM1 ) overexpression in relevant mouse models. Early systemic MTM1 overexpression prevented the development of the CNM pathology in Bin1mck-/- mice, while late intramuscular MTM1 expression partially reverted the established phenotypes after only 4 weeks of treatment. However, AAV-MTM1 injection did not change the DNM2-CNM mouse phenotypes. We investigated the mechanism of the rescue of the myopathy in BIN1-CNM and found that the lipid phosphatase activity of MTM1 was essential for the rescue of muscle atrophy and myofibre hypotrophy but dispensable for the rescue of myofibre disorganization including organelle mis-position and T-tubule defects. Furthermore, the improvement of T-tubule organization correlated with normalization of key regulators of T-tubule morphogenesis, dysferlin and caveolin. Overall, these data support the inclusion of BIN1-CNM patients in an AAV-MTM1 clinical trial.
Fichier principal
Vignette du fichier
islandora_171543.pdf (1.98 Mo) Télécharger le fichier
Origin Publication funded by an institution

Dates and versions

hal-04673216 , version 1 (19-08-2024)

Identifiers

Cite

Quentin Giraud, Coralie Spiegelhalter, Nadia Messaddeq, Jocelyn Laporte. MTM1 overexpression prevents and reverts BIN1-related centronuclear myopathy. Brain - A Journal of Neurology , 2023, 146 (10), pp.4158-4173. ⟨10.1093/brain/awad251⟩. ⟨hal-04673216⟩
20 View
2 Download

Altmetric

Share

More