Human Molecular Genetics Advance Access originally published online on April 22, 2008
Human Molecular Genetics 2008 17(14):2132-2143; doi:10.1093/hmg/ddn112
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AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis
1 Department of Neurobiology and Genetics 2 Imaging Center – Electron Microscopy 3 Department of Structural Biology and Genomics, Institut de Génétique et de Biologie, Moléculaire et Cellulaire (IGBMC), INSERM U596, CNRS UMR 7104, Université Louis Pasteur de Strasbourg, Collège de France, 67404 Illkirch, France 4 Généthon, R&D Department, 1 rue de l’Internationale, 91000 Evry 5 Children’s Hospital, Harvard Medical School, Boston, USA
* To whom correspondence should be addressed at: Department of Neurobiology and Genetics, Institut de Génétique et de Biologie, Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404 Illkirch, France. Tel: +33 388653244; Fax: +33 388653246; Email: mtm{at}igbmc.u-strasbg.fr
Received December 10, 2007; Accepted April 8, 2008
Myotubular myopathy (XLMTM, OMIM 310400 [OMIM] ) 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.
Present address: Research Institute at Nationwide Children’s Hospital, Columbus, USA.
Present address: INSERM U781, Hôpital Necker-Enfants Malades, Paris, France.
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