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 |
dc.identifier.doi | 10.1093/hmg/ddn112 | * |
dash.authorsordered | false | |
dash.contributor.affiliated | Beggs, Alan | |