L-arginine improves dystrophic phenotype in mdx mice.
A possible treatment for Duchenne muscular dystrophies would be to compensate for dystrophin loss by increasing the expression of utrophin, another cytoskeletal protein of the muscle membrane. We previously found that L-arginine, the substrate for nitric oxide synthase, significantly increased utrophin level in muscle and targeted it to the sarcolemma. Here, we have addressed the expected benefit in the mdx mice. Magnetic resonance imaging of lower limbs revealed a 35% reduction of the necrotic zones, confirmed by histological staining of muscles. This regression of the necrosis was also supported by the drastic reduction of Evans blue incorporation, a cell impermeable dye. The creatine kinase level in the serum decreased by 57%. Utrophin level increased 2- to 3-fold in muscles. Beta-dystroglycan was relocalised with utrophin to the membrane. In the diaphragm, the most affected muscle in mdx mice, the isometric tension increased by 30%, with regression of collagen and of cytoplasmic lipid overloading. Finally, molsidomine, a therapeutic agent that is converted to a NO donor, also attenuated the dystrophic phenotype. Our results suggest that pharmacological activators of the NO pathway may constitute a realistic treatment for Duchenne and Becker muscular dystrophies.
Voisin
Vincent
V
Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS UPR 9040, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France.
Sébrié
Catherine
C
Matecki
Stéfan
S
Yu
Hua
H
Gillet
Brigitte
B
Ramonatxo
Michèle
M
Israël
Maurice
M
De la Porte
Sabine
S
D000818:Animals; D001120:Arginine / Q000494:pharmacology* / Q000627:therapeutic use; D003402:Creatine Kinase / Q000097:blood; D003964:Diaphragm / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism; D005070:Evans Blue; D005260:Female; D007537:Isometric Contraction / Q000187:drug effects / Q000235:genetics; D008279:Magnetic Resonance Imaging; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009336:Necrosis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010641:Phenotype; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D016896:Treatment Outcome; D049411:Utrophin / Q000378:metabolism
D020030:Nitric Oxide Donors; D049411:Utrophin; D049030:Dystroglycans; D005070:Evans Blue; D001120:Arginine; D003402:Creatine Kinase