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 utrop...
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doaj-8f11f0c88a914c9e8f33fb4a69c657462021-03-20T04:51:05ZengElsevierNeurobiology of Disease1095-953X2005-10-01201123130l-arginine improves dystrophic phenotype in mdx miceVincent Voisin0Catherine Sébrié1Stéfan Matecki2Hua Yu3Brigitte Gillet4Michèle Ramonatxo5Maurice Israël6Sabine De la Porte7Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS UPR 9040, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, FranceInstitut de Chimie des Substances Naturelles CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, FranceLaboratoire de Physiologie, Hôpital Arnaud de Villeneuve, 34265 Montpellier, FranceLaboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS UPR 9040, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, FranceInstitut de Chimie des Substances Naturelles CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, FranceLaboratoire de Physiologie, Hôpital Arnaud de Villeneuve, 34265 Montpellier, FranceLaboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS UPR 9040, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, FranceLaboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS UPR 9040, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France; Corresponding author. Fax: +33 1 69 82 41 41.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. β-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.http://www.sciencedirect.com/science/article/pii/S0969996105000677UtrophinDystrophinmdxDMDl-arginineMolsidomine |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vincent Voisin Catherine Sébrié Stéfan Matecki Hua Yu Brigitte Gillet Michèle Ramonatxo Maurice Israël Sabine De la Porte |
spellingShingle |
Vincent Voisin Catherine Sébrié Stéfan Matecki Hua Yu Brigitte Gillet Michèle Ramonatxo Maurice Israël Sabine De la Porte l-arginine improves dystrophic phenotype in mdx mice Neurobiology of Disease Utrophin Dystrophin mdx DMD l-arginine Molsidomine |
author_facet |
Vincent Voisin Catherine Sébrié Stéfan Matecki Hua Yu Brigitte Gillet Michèle Ramonatxo Maurice Israël Sabine De la Porte |
author_sort |
Vincent Voisin |
title |
l-arginine improves dystrophic phenotype in mdx mice |
title_short |
l-arginine improves dystrophic phenotype in mdx mice |
title_full |
l-arginine improves dystrophic phenotype in mdx mice |
title_fullStr |
l-arginine improves dystrophic phenotype in mdx mice |
title_full_unstemmed |
l-arginine improves dystrophic phenotype in mdx mice |
title_sort |
l-arginine improves dystrophic phenotype in mdx mice |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2005-10-01 |
description |
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. β-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. |
topic |
Utrophin Dystrophin mdx DMD l-arginine Molsidomine |
url |
http://www.sciencedirect.com/science/article/pii/S0969996105000677 |
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