Nitric oxide and l-arginine cause an accumulation of utrophin at the sarcolemma: a possible compensation for dystrophin loss in Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD), a severe X-linked recessive disorder which results in progressive muscle degeneration, is due to a lack of dystrophin, a membrane cytoskeletal protein. An approach to treatment is to compensate for dystrophin loss with utrophin, another cytoskeletal protein with over 80% homology with dystrophin. Utrophin is expressed, at the neuromuscular junction, in normal and DMD muscles and there is evidence that it may perform the same cellular functions as dystrophin. So, the identification of molecules or drugs that could up-regulate utrophin is a very important goal for therapy. We show that in adult normal and mdx mice (an animal model of Duchenne myopathy) treated with l-arginine, the substrate of nitric oxide synthase (NOS), a pool of utrophin localized at the membrane appeared and increased, respectively. In normal and mdx myotubes in culture, l-arginine, nitric oxide (NO), or hydroxyurea increased utrophin levels and enhanced its membrane localization. This effect did not occur with d-arginine, showing the involvement of NOS in this process. The NO-induced increase in utrophin was prevented by oxadiazolo-quinoxalin-1-one, an inhibitor of a soluble guanylate cyclase implicated in NO effects. These results open the way to a potential treatment for Duchenne and Becker dystrophies.
Chaubourt
E
E
Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS, Gif sur Yvette Cedex, 91198, France.
Fossier
P
P
Baux
G
G
Leprince
C
C
Israël
M
M
De La Porte
S
S
D000818:Animals; D001120:Arginine / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D016189:Dystrophin / Q000378:metabolism*; D006918:Hydroxyurea / Q000009:adverse effects; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008981:Molsidomine / Q000009:adverse effects / Q000031:analogs & derivatives; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000009:adverse effects; D049411:Utrophin
D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; C483600:Utrn protein, mouse; D049411:Utrophin; D009569:Nitric Oxide; C002385:linsidomine; D001120:Arginine; D008981:Molsidomine; D006918:Hydroxyurea