title: Muscular nitric oxide synthase (muNOS) and utrophin.
abstract: Duchenne muscular dystrophy (DMD), the severe X-linked recessive disorder which results in progressive muscle degeneration, is due to a lack of dystrophin, a membrane cytoskeletal protein. Three types of treatment are envisaged: pharmacological (glucocorticoid), myoblast transplantation, and gene therapy. An alternative to the pharmacological approach is to compensate for dystrophin loss by the upregulation of another cytoskeletal protein, utrophin. Utrophin and dystrophin are part of a complex of proteins and glycoproteins, which links the basal lamina to the cytoskeleton, thus ensuring the stability of the muscle membrane. One protein of the complex, syntrophin, is associated with a muscular isoform of the neuronal nitric oxide synthase (nNOS). We have demonstrated an overexpression of utrophin, visualised by immunofluorescence and quantified by Western blotting, in normal myotubes and in mdx (the animal model of DMD) myotubes, as in normal (C57) and mdx mice, both treated with nitric oxide (NO) donor or L-arginine, the NOS substrate. There is evidence that utrophin may be capable of performing the same cellular functions as dystrophin and may functionally compensate for its lack. Thus, we propose to use NO donors, as palliative treatment of Duchenne and Becker muscular dystrophies, pending, or in combination with, gene and/or cellular therapy. Discussion has focussed on the various isoforms of NOS that could be implicated in the regeneration process. Dystrophic and healthy muscles respond to treatment, suggesting that although NOS is delocalised in the cytoplasm in the case of DMD, it conserves substantial activity. eNOS present in mitochondria and iNOS present in cytoplasm and the neuromuscular junction could also be activated. Lastly, production of NO by endothelial NOS of the capillaries would also be beneficial through increased supply of metabolites and oxygen to the muscles.
authors.affiliation: Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS UPR 9040, Avenue de la Terrasse, 91198 Gif sur Yvette cedex, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chaubourt
authors.forename: Vincent
authors.initials: V
authors.lastname: Voisin
authors.forename: Philippe
authors.initials: P
authors.lastname: Fossier
authors.forename: Gérard
authors.initials: G
authors.lastname: Baux
authors.forename: Maurice
authors.initials: M
authors.lastname: Israël
authors.forename: Sabine
authors.initials: S
authors.lastname: De La Porte
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012016:Reference Values; D013848:Thigh; D049411:Utrophin; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; C483600:Utrn protein, mouse; D049411:Utrophin; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase