title: Combination of myostatin pathway interference and dystrophin rescue enhances tetanic and specific force in dystrophic mdx mice.
abstract: Duchenne muscular dystrophy is characterized by muscular atrophy, fibrosis, and fat accumulation. Several groups have demonstrated that in the mdx mouse, the exon-skipping strategy can restore a quasi-dystrophin in almost 100% of the muscle fibers. On the other hand, inhibition of the myostatin pathway in adult mice has been described to enhance muscle growth and improve muscle force. Our aim was to combine these two strategies to evaluate a possible additive effect. We have chosen to inhibit the myostatin pathway using the technique of RNA interference directed against the myostatin receptor AcvRIIb mRNA (sh-AcvRIIb). The restoration of a quasi-dystrophin was mediated by the vectorized U7 exon-skipping technique (U7-DYS). Adeno-associated vectors carrying either the sh-AcvrIIb construct alone, the U7-DYS construct alone, or a combination of both constructs were injected in the tibialis anterior (TA) muscle of dystrophic mdx mice. We show that even if each separate approach has some effects on muscle physiology, the combination of the dystrophin rescue and the downregulation of the myostatin receptor is required to massively improve both the tetanic force and the specific force. This study provides a novel pharmacogenetic strategy for treatment of certain neuromuscular diseases associated with muscle wasting.
authors.affiliation: INSERM U974, UMR 7215 CNRS, Institut de Myologie, UM 76 Université Pierre et Marie Curie, Paris, France. julie.dumonceaux@upmc.fr
authors.forename: Julie
authors.initials: J
authors.lastname: Dumonceaux
authors.forename: Solenne
authors.initials: S
authors.lastname: Marie
authors.forename: Cyriaque
authors.initials: C
authors.lastname: Beley
authors.forename: Capucine
authors.initials: C
authors.lastname: Trollet
authors.forename: Alban
authors.initials: A
authors.lastname: Vignaud
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
authors.forename: Luis
authors.initials: L
authors.lastname: Garcia
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000628:therapy*; D055435:Myostatin / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D016189:Dystrophin; D055435:Myostatin; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B