Dystrophin threshold level necessary for normalisation of nNOS, iNOS and RyR1 nitrosylation in GRMD dystrophinopathy
| Autor: | Gentil, Christel, Le Guiner, Caroline, Falcone, Sestina, Hogrel, Jean-Yves, Peccate, Cecile, Lorain, Stéphanie, Benkhelifa-Ziyyat, Sofia, Guigand, Lydie, Montus, Marie-Françoise, Servais, Laurent, Voit, Thomas, Pietri-Rouxel, France |
|---|---|
| Přispěvatelé: | Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Atlantic Gene Therapies, Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Généthon, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
musculoskeletal diseases
congenital hereditary and neonatal diseases and abnormalities [SDV.GEN]Life Sciences [q-bio]/Genetics myopathie de duchenne chien GRMD Médecine humaine et pathologie oxyde nitrique synthase saut d'exon musculoskeletal system thérapie génique canal calcique dystrophine Human health and pathology [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Human Gene Therapy Human Gene Therapy, 2016, 27 (9), pp.712-726. ⟨10.1089/hum.2016.041⟩ Human Gene Therapy, Mary Ann Liebert, 2016, 27 (9), pp.712-726. ⟨10.1089/hum.2016.041⟩ Human Gene Therapy 9 (27), 712-726. (2016) |
| ISSN: | 1043-0342 |
| DOI: | 10.1089/hum.2016.041⟩ |
| Popis: | International audience; Currently, the clinically most advanced strategy to treat Duchenne muscular dystrophy (DMD) is the exon skipping strategy. Whereas antisense oligonucleotide-based clinical trials are underway for DMD, it is essential to determine a dystrophin restoration threshold needed to ensure improvement of muscle physiology at the molecular level. A preclinical trial was recently conducted in golden retriever muscular dystrophy (GRMD) dogs treated in a forelimb by locoregional delivery of rAAV8-U7snRNA to promote exon skipping on the canine dystrophin messenger. Here, we exploited the rAAV8-U7snRNA transduced GRMD muscle samples, well-characterized for their percentage of dystrophin-positive fibers, in the aim to define a threshold of dystrophin rescue necessary for normalization of the status of the neuronal nitric oxide synthase mu (nNOSµ), the inducible nitric oxide synthase (iNOS), and the ryanodine receptor-calcium release channel type 1 (RyR1), crucial actors for an efficient contractile function. Results showed that the restoration of dystrophin in 40% of muscle fibers is needed to decrease the abnormal cytosolic nNOSµ expression and to reduce the overexpression of iNOS, these two parameters leading to a reduction of the NO level into the muscle fiber. Furthermore, the same percentage of dystrophin-positive fibers of 40 % was associated with the normalization of the RyR1 nitrosylation status and to a stabilization of the RyR1/calstabin1 complex that is required to facilitate coupled gating. We concluded that a minimal threshold of 40% of dystrophin-positive fibers is necessary for the reinstatement of central proteins needed for a proper muscle contractile function, and thus identified a rate of dystrophin expression significantly improving, at the molecular level, the dystrophic muscle physiology. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|