Résumé :
|
Carinne Roudaut1, William Lostal1, Marc Bartoli4, Nathalie Bourg1, Martin Krahn4, Marina Pryadkina1, Perrine Borel1, Laurence Suel1, Joseph Roche2, Daniel Stockholm1 Robert Bloch2, Nicolas Levy4, Rumaisa Bashir3, Isabelle Richard11) Genethon, CNRS UMR8587 LAMBE, 1, rue de l'Internationale, 91000 Evry, France2) University of Maryland, U.S.3) School of Biological and Biomedical Sciences South Road, Durham, DH1 3LE, U.K.4) Drtement de Gtique Mcale, Hpital d'Enfants de la Timone, AP-HM, and Inserm UMR_S 910, Facult Mcine Timone, Universit la Mterran Marseille, FranceMutations in dysferlin are the cause of Limb-girdle Muscular Dystrophy type 2B and Miyoshi Myopathy. This protein has been implicated in sarcolemmal resealing, leading to the assumption that the pathophysiology of dysferlin deficiencies is due to a deficit in membrane repair. Here, we show using two different approaches that dysferlin has role other than repairing the sarcolemma. First, we generated a transgenic model overexpressing myoferlin to test the hypothesis that myoferlin, which is homologous to dysferlin, can compensate for the absence of dysferlin. The myoferlin overexpressors show no muscle abnormalities, and, crossing them with a dysferlin-deficient model, rescues the membrane fusion defect present in dysferlin-deficient mice. However, this compensation does not result in improvedin muscle histology. Second, we showed that AAV-mediated transfer of a minidysferlin that corresponds to the end of the dysferlin protein and that was previously shown to correct the membrane repair deficit, as assayed by laser wounding, also failed to improve muscle histology. Furthermore, neither myoferlin nor the minidysferlin prevented damage to dysferlin-null muscle following eccentric exercise. Our data indicate that the pathogenicity of dysferlin deficiency is not related directly to impairment in sarcolemmal repair and that the function of dysferlin goes beyond membrane resealing.
|