AAV-Mediated Intramuscular Delivery of Myotubularin Corrects the Myotubular Myopathy Phenotype in Targeted Murine Muscle and Suggests a Function in Plasma Membrane Homeostasis

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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

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dc.contributor.author Buj-Bello, Anna
dc.contributor.author Fougerousse, Françoise
dc.contributor.author Schwab, Yannick
dc.contributor.author Messaddeq, Nadia
dc.contributor.author Spehner, Danièle
dc.contributor.author Pierson, Christopher R.
dc.contributor.author Durand, Muriel
dc.contributor.author Kretz, Christine
dc.contributor.author Danos, Olivier
dc.contributor.author Douar, Anne-Marie
dc.contributor.author Schultz, Patrick
dc.contributor.author Montus, Marie
dc.contributor.author Denèfle, Patrice
dc.contributor.author Mandel, Jean-Louis
dc.contributor.author Beggs, Alan Hendrie
dc.date.accessioned 2012-02-19T23:23:30Z
dc.date.issued 2008
dc.identifier.citation Buj-Bello, Anna, Françoise Fougerousse, Yannick Schwab, Nadia Messaddeq, Danièle Spehner, Christopher R. Pierson, Muriel Durand, et al. 2008. AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis. Human Molecular Genetics 17(14): 2132-2143. en_US
dc.identifier.issn 0964-6906 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8191177
dc.description.abstract 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. en_US
dc.language.iso en_US en_US
dc.publisher Oxford University Press en_US
dc.relation.isversionof doi:10.1093/hmg/ddn112 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441725/pdf/ en_US
dash.license LAA
dc.title AAV-Mediated Intramuscular Delivery of Myotubularin Corrects the Myotubular Myopathy Phenotype in Targeted Murine Muscle and Suggests a Function in Plasma Membrane Homeostasis en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Human Molecular Genetics en_US
dash.depositing.author Beggs, Alan Hendrie
dc.date.available 2012-02-19T23:23:30Z
dash.affiliation.other HMS^Pediatrics-Children's Hospital en_US

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