Résumé :
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Centronuclear myopathies (CNM) are congenital myopathies characterized by an abnormal central localization of the nuclei in skeletal muscle fibres associated with a generalized muscle weakness and atrophy. The X-linked, also named myotubular myopathy is the most severe form characterised by generalized hypotonia without cardiac involvement. This form is due to mutations in the MTM1 gene encoding the 3-phosphoinositides phosphatase myotubularin (MTM1). We demonstrated that MTM1 is an intermediate filaments (IFs)-binding protein and provide evidence for direct regulation of the muscle specific IF desmin by MTM1 in vitro and in vivo. Mutations in the DES gene lead to desmin-related myopathy and cardiomyopathy. XLCNM-causing mutations in MTM1 disrupted the MTM1-desmin complex, resulting in abnormal IF assembly and architecture in muscle cells and both mouse and human skeletal muscles. In addition, decreased MTM1 expression and XLCNM-causing mutations induced abnormal mitochondrial positioning, shape, and dynamics. 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 XLCNM and desmin-related myopathies. In addition to MTM1-desmin complex in skeletal muscle, it was shown that MTMR2, a close homologue of MTM1, and the neurofilament light chain protein (NF-L) could interact in vivo in peripheral nerve. Both MTMR2 and NF-L are mutated in Charcot-Marie-Tooth neuropathies (CMT4B1 for MTMR2 and CMT2E and CMT1 for NF-L). Interaction between three myotubularins (MTM1, MTMR1, MTMR2) and three IF proteins (Desmin, Vimentin and NF-L) revealed that, while MTMR1 can bind all the IFs, MTM1 bind to desmin and vimentin and MTMR2 bind to NF-L. These findings suggest that specific myotubularins-IFs complexes underlie the tissue specificity of the related disorders: MTM1-desmin in myopathies and MTMR2-NF-L in neuropathies. The interaction of MTM1 with vimentin could be relevant in muscle at the foetal stages where both proteins are expressed. Interestingly, fibroblast cell lines from XLCNM patients have a compacted/aggregating vimentin network. As proved before for muscle cells, we observed also defects in mitochondrial distribution defects and decreased cytochrome C oxidase activity in these cells. This result suggests that the myotubularins-IFs interaction is also crucial for mitochondrial homeostasis and dynamics in non-muscle cells.
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