Résumé :
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Myotubularin (MTM1) is a phosphoinositides 3-phosphatase regulating phosphatidylinositol 3-phosphate (PtdIns3P) and mutated in X-linked myotubular (centronuclear) myopathy. While MTM1 is ubiquitously expressed, the importance of its activity in skeletal muscle and in the pathology was not investigated. We characterized the murine MTM1 knock-out model that reproduces faithfully the histopathological findings from human patients. Re-expression of phosphatase-inactive MTM1 mutants with Adeno-associated virus improved most phenotypes, to a similar extend compared to wild-type MTM1. Mass assay measurement of PtdIns3P showed this rescue was not correlated to a normalization of PtdIns3P level. However, phosphatase inactive mutants of MTM1 did not rescue fully the aberrant shape of triads, membrane structures underlying excitation-contraction coupling. In vivo manipulation of PtdIns3P level in muscle from wild-type mice and subcellular localization of PtdIns3P confirmed an important role of PtdIns3P in triad membrane shape. These findings support a phosphatase-independent role of MTM1 in the general organization of skeletal muscle, while PtdIns3P is implicated in membrane curvature at the triad.
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