P.4.2 MTMR2 ameliorates the phenotype of myotubular myopathy in mice

Abstract

X-linked myotubular myopathy is the most severe form of centronuclear myopathy, a group of rare muscular diseases characterized by the presence of nuclei in central position of hypotrophic myofibres. Male patients present at birth with profound muscle hypotonia and weakness, respiratory insufficiency, and often die prematurely. The pathology is caused by mutations in the MTM1 gene. Myotubularin, the encoded protein, is a 3-phosphoinositide phosphatase founding a family of homologous proteins, the MTMRs (myotubularin-related-proteins). In order to develop a therapy for myotubular myopathy, we tested the ability of Mtmr1 and Mtmr2 genes, the closest Mtm1 homologues, to rescue the phenotype of myotubularin-deficient mice. AAV2/9 vectors encoding MTMR1, MTMR2 or myotubularin were injected in the tibialis anterior of two week-old symptomatic mtm1-KO mice. A therapeutic effect was observed after two weeks with Mtmr2 but not with Mtmr1 overexpression. Muscle weight and myofibres diameters were increased, indicating a partial correction of hypotrophy and histopathological hallmarks were normalised. Importantly, the force of myotubularin-deficient muscles also improved after Mtmr2 delivery. Altogether, these results suggest that skeletal muscle-targeted MTMR2 overexpression may represent a powerful therapeutic strategy for myotubular myopathy.