AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis

• Published in: Human molecular genetics Vol. 17; no. 14; pp. 2132 - 2143
• Main Authors: Buj-Bello, Anna, Fougerousse, Françoise, Schwab, Yannick, Messaddeq, Nadia, Spehner, Danièle, Pierson, Christopher R., Durand, Muriel, Kretz, Christine, Danos, Olivier, Douar, Anne-Marie, Beggs, Alan H., Schultz, Patrick, Montus, Marie, Denèfle, Patrice, Mandel, Jean-Louis
• Format: Journal Article
• Language: English
• Published: Oxford University Press (OUP) 22-04-2008
• Subjects: Animals; Biochemistry, Molecular Biology; Cell Line; Cell Membrane; Dependovirus; Female; Gene Therapy; Genetic Vectors; Homeostasis; Injections, Intramuscular; Life Sciences; Male; Mice; Muscle, Skeletal; Myopathies, Structural, Congenital; Phenotype; Protein Tyrosine Phosphatases, Non-Receptor
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddn112

Myotubular myopathy (XLMTM, OMIM 310400) is a severe congenital muscular disease due to mutations in the myotubularin gene (MTM1) and characterized by the presence of small myofibers with frequent occurrence of central nuclei. Myotubularin is a ubiquitously expressed phosphoinositide phosphatase with a muscle-specific role in man and mouse that is poorly understood. No specific treatment exists to date for patients with myotubular myopathy. We have constructed an adeno-associated virus (AAV) vector expressing myotubularin in order to test its therapeutic potential in a XLMTM mouse model. We show that a single intramuscular injection of this vector in symptomatic Mtm1-deficient mice ameliorates the pathological phenotype in the targeted muscle. Myotubularin replacement in mice largely corrects nuclei and mitochondria positioning in myofibers and leads to a strong increase in muscle volume and recovery of the contractile force. In addition, we used this AAV vector to overexpress myotubularin in wild-type skeletal muscle and get insight into its localization and function. We show that a substantial proportion of myotubularin associates with the sarcolemma and I band, including triads. Myotubularin overexpression in muscle induces the accumulation of packed membrane saccules and presence of vacuoles that contain markers of sarcolemma and T-tubules, suggesting that myotubularin is involved in plasma membrane homeostasis of myofibers. This study provides a proof-of-principle that local delivery of an AAV vector expressing myotubularin can improve the motor capacities of XLMTM muscle and represents a novel approach to study myotubularin function in skeletal muscle.