MTM1 overexpression prevents and reverts BIN1-related centronuclear myopathy.
Animals
Humans
Mice
Adaptor Proteins, Signal Transducing
/ genetics
Dynamin II
/ genetics
Lipids
Muscle, Skeletal
/ pathology
Muscular Atrophy
/ pathology
Mutation
Myopathies, Structural, Congenital
/ genetics
Nuclear Proteins
/ genetics
Phenotype
Tumor Suppressor Proteins
/ genetics
Protein Tyrosine Phosphatases, Non-Receptor
/ genetics
Genetic Therapy
congenital myopathy
gene therapy
mTOR
neuromuscular disease
skeletal muscle
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
03 10 2023
03 10 2023
Historique:
received:
23
12
2022
revised:
30
06
2023
accepted:
06
07
2023
medline:
4
10
2023
pubmed:
25
7
2023
entrez:
25
7
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37490306
pii: 7230727
doi: 10.1093/brain/awad251
pmc: PMC10545525
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
BIN1 protein, human
0
Dynamin II
EC 3.6.5.5
Lipids
0
Nuclear Proteins
0
Tumor Suppressor Proteins
0
myotubularin
EC 3.1.3.48
Protein Tyrosine Phosphatases, Non-Receptor
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4158-4173Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.
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