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(American Journal of Pathology. 2007;170:633-643.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060344

Modulation of p38 Mitogen-Activated Protein Kinase Cascade and Metalloproteinase Activity in Diaphragm Muscle in Response to Free Radical Scavenger Administration in Dystrophin-Deficient Mdx Mice

Karim Hnia^*, Gerald Hugon^*, François Rivier^*, Ahmed Masmoudi, Jacques Mercier^* and Dominique Mornet^*

From Institut National de la Santé et de la Recherche Médicale, Equipe ERI 25, Muscle et Pathologies, Université de Montpelier1, Unité de Formation et de Recherche de Médecine,^* EA701, Montpellier, France; and the Institut Supérieur de Biotechnologie, Laboratoire de Biochimie, Faculté de Médecine, Monastir, Tunisia

Duchenne muscular dystrophy muscles undergo increased oxidative stress and altered calcium homeostasis, which contribute to myofiber loss by trigging both necrosis and apoptosis. Here, we asked whether treatment with free radical scavengers could improve the dystrophic pattern of mdx muscles. Five-week-old mdx mice were treated for 2 weeks with -lipoic acid/L-carnitine. This treatment decreased the plasmatic creatine kinase level, the antioxidant enzyme activity, and lipid peroxidation products in mdx diaphragm. Free radical scavengers also modulated the phosphorylation/activity of some component of the mitogen-activated protein kinase (MAPK) cascades: p38 MAPK, the extracellular signal-related kinase, and the Jun kinase. ß-Dystroglycan (ß-DG), a multifunctional adaptor or scaffold capable of interacting with components of the extracellular signal-related kinase-MAP kinase cascade, was also affected after treatment. In the mdx muscles, ß-DG (43 kd) was cleaved by matrix metalloproteinases into a 30-kd form (ß-DG₃₀). We show that the proinflammatory protein nuclear factor-B activator decreased after the treatment, leading to a significant reduction of matrix metalloproteinase activity in the mdx diaphragm. Our data highlight the implication of oxidative stress and cell signaling defects in dystrophin-deficient muscle via the MAP kinase cascade-ß-DG interaction and nuclear factor-B-mediated inflammation process.

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