Résumé :
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Myotubular myopathy (XLMTM) is a severe congenital disease that affects skeletal musculature, which is characterized by the presence of small myofibres with frequent occurrence of central nuclei. The disease is due to mutations in the MTM1 gene, encoding a phosphoinositide phosphatase named myotubularin. Specific treatment is currently unavailable. We have previously demonstrated that a single intramuscular injection of an adeno-associated virus (AAV) vector expressing myotubularin under the cytomegalovirus (CMV) promoter in symptomatic muscle-specific Mtm1-deficient mice ameliorates the phenotype in targeted muscles. We have now extended these gene transfer assays also to constitutive (KO) Mtm1 mutants and used a novel serotype 1 AAV vector that contains the desmin promoter for muscle-specific expression of myotubularin (AAV1-Des-Mtm1). In addition, since muscle hypotrophy correlates with prognosis severity, we investigated the effect of a rAAV vector that expresses a dominant negative mutated myostatin propeptide (AAV1-CMV-PropD76A) either alone or together with Mtm1 delivery. Vectors were injected into the tibialis anterior muscle of 3 week-old Mtm1 KO mice and muscles were analyzed 2 weeks later. We found that intramuscular injection of the AAV1-Des-Mtm1 vector leads to an important improvement of the pathology and function of targeted muscles. Injection of the AAV1-CMV-PropD76A vector alone in XLMTM muscles has no effect on muscle mass. However, when this vector was co-administrated with Mtm1, it leads to a significant 30% increase in the tibialis anterior muscle weight. Myofiber diameter is also increased and the normal distribution of internal organelles, such as nuclei, mitochondria and triad markers, is restored. The effect of this co-treatment in the contractile force of muscles from mutant mice is currently being explored. Altogether, we demonstrate that AAV-mediated inhibition of the myostatin pathway potentiates Mtm1 gene therapy, which could be of relevance for the development of a therapeutic strategy for the disease.
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