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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Author
Buj-Bello, Anna
Fougerousse, Françoise
Schwab, Yannick
Messaddeq, Nadia
Spehner, Danièle
Pierson, Christopher R.
Durand, Muriel
Kretz, Christine
Danos, Olivier
Douar, Anne-Marie
Schultz, Patrick
Montus, Marie
Denèfle, Patrice
Mandel, Jean-Louis
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1093/hmg/ddn112Metadata
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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.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441725/pdf/Terms of Use
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http://nrs.harvard.edu/urn-3:HUL.InstRepos:8191177
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