期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 121, 期 1, 页码 70-85出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI44021
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资金
- INSERM
- CNRS
- University of Strasbourg
- College de France
- Association Francaise contre les Myopathies (AFM) [AFM 11063, 12323, 12967, 13591, 14204]
- Fondation Recherche Medicale [DEQ20071210538]
- GIS Institut Maladies Rares
- Agence Nationale de la Recherche (ANR) [ANR 07 BLAN 0065 01, ANR 08 GENOPAT 005]
- NIH [P50 NS040828]
- Joshua Frase Foundation
- Lee and Penny Anderson Family Foundation
- Muscular Dystrophy Association
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P50NS040828] Funding Source: NIH RePORTER
Muscle contraction relies on a highly organized intracellular network of membrane organelles and cytoskeleton proteins Among the latter are the intermediate filaments (IFs), a large family of proteins mutated in more than 30 human diseases For example, mutations in the DES gene, which encodes the IF desmin, lead to desmin-related myopathy and cardiomyopathy Here, we demonstrate that myotubularin (MTM1), which is mutated in individuals with X-linked centronuclear myopathy (XLCNM, also known as myotubular myopathy), is a desmin-binding protein and provide evidence for direct regulation of desmin by MTM1 in vitro and in vivo XLCNM-causing mutations in MTM1 disrupted the MTM1-desmin complex, resulting m abnormal IF assembly and architecture in muscle cells and both mouse and human skeletal muscles Adeno-associated virus-mediated ectopic expression of WT MTM1 in Mtm1-KO muscle reestablished normal desmin expression and localization In addition, decreased MTM1 expression and XLCNM-causing mutations induced abnormal mitochondrial positioning, shape, dynamics, and function We therefore conclude that MTM1 is a major regulator of both the desmin cytoskeleton and mitochondria homeostasis, specifically in skeletal muscle Defects in IF stabilization and mitochondrial dynamics appear as common physiopathological features of centronuclear myopathies and desmin-related myopathies
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