title: AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis.
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.
authors.affiliation: Department of Neurobiology and Genetics, , INSERM U596, CNRS UMR 7104, Université Louis Pasteur de Strasbourg, Collège de France, 67404 Illkirch, France. mtm@igbmc.u-strasbg.fr
authors.forename: Anna
authors.initials: A
authors.lastname: Buj-Bello
authors.forename: Françoise
authors.initials: F
authors.lastname: Fougerousse
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schwab
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.forename: Danièle
authors.initials: D
authors.lastname: Spehner
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.forename: Muriel
authors.initials: M
authors.lastname: Durand
authors.forename: Christine
authors.initials: C
authors.lastname: Kretz
authors.forename: Olivier
authors.initials: O
authors.lastname: Danos
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Douar
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.forename: Patrick
authors.initials: P
authors.lastname: Schultz
authors.forename: Marie
authors.initials: M
authors.lastname: Montus
authors.forename: Patrice
authors.initials: P
authors.lastname: Denèfle
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006706:Homeostasis; D007273:Injections, Intramuscular; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D010641:Phenotype; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000008:administration & dosage / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
chemical_list: D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin