Résumé :
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X-linked Myotubular Myopathy (XLMTM) is the most severe form of centronuclear myopathy, a group of muscular diseases classified together in reason of the presence of abnormally large nuclei localized in central position of hypotrophic myofibres. XLMTM patients present at birth with profound muscle hypotonia and weakness, respiratory insufficiency, and often die prematurely. The pathology is caused by inactivating mutations in MTM1, the gene encoding myotubularin, a lipid phosphatase showing PI3P and PI3,5P2 substrate specificity. MTM1 belongs to a large neuromuscular disease-associated gene family composed of 15 members (MTMR1-14) in humans, with MTMR2 and MTMR13 mutations causing Charcot-Marie-Tooth type 4B1 and 4B2 neuropathies, respectively. In the present study, we tested the ability of Mtmr2, the closest Mtm1 homologue by sequence identity, to rescue the motor abnormalities observed in myotubularin deficient mice. For that purpose, we injected a recombinant serotype 1 adeno-associated vector expressing Mtmr2 under the desmin promoter (rAAV2/1-Des-Mtmr2) in both EDL and tibialis anterior muscles of three-week-old myotubularin KO mice. Preliminary results show that, two weeks after vector delivery, muscle weight and myofiber diameter increase slightly in both treated muscles. We also measured the strength of isolated EDL muscles and found a partial recovery of the isometric specific force of AAV-treated KO muscles. These results suggest that Mtmr2 overexpression in skeletal muscle may represent an alternative strategy for treating Mtm1 deficiency.
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