Published online before print May 5, 2008

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(American Journal of Pathology. 2008;172:1509-1519.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071009

L-Arginine Decreases Inflammation and Modulates the Nuclear Factor-B/Matrix Metalloproteinase Cascade in Mdx Muscle Fibers

Karim Hnia^*, Jérôme Gayraud^*, Gérald Hugon^*, Michèle Ramonatxo^*, Sabine De La Porte, Stefan Matecki^* and Dominique Mornet^*

From INSERM ERI 25 Muscle et Pathologies,^* Chu A. de Villeneuve, Université de Montpellier1, Montpellier; and the Laboratoire de Neurobiologie Cellulaire et Moléculaire, Centre National de la Recherche Scientifique UPR 9040, Gif sur Yvette, France

Duchenne muscular dystrophy (DMD) is a lethal, X-linked disorder associated with dystrophin deficiency that results in chronic inflammation, sarcolemma damage, and severe skeletal muscle degeneration. Recently, the use of L-arginine, the substrate of nitric oxide synthase (nNOS), has been proposed as a pharmacological treatment to attenuate the dystrophic pattern of DMD. However, little is known about signaling events that occur in dystrophic muscle with L-arginine treatment. Considering the implication of inflammation in dystrophic processes, we asked whether L-arginine inhibits inflammatory signaling cascades. We demonstrate that L-arginine decreases inflammation and enhances muscle regeneration in the mdx mouse model. Classic stimulatory signals, such as proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-, are significantly decreased in mdx mouse muscle, resulting in lower nuclear factor (NF)-B levels and activity. NF-B serves as a pivotal transcription factor with multiple levels of regulation; previous studies have shown perturbation of NF-B signaling in both mdx and DMD muscle. Moreover, L-arginine decreases the activity of metalloproteinase (MMP)-2 and MMP-9, which are transcriptionally activated by NF-B. We show that the inhibitory effect of L-arginine on the NF-B/MMP cascade reduces β-dystroglycan cleavage and translocates utrophin and nNOS throughout the sarcolemma. Collectively, our results clarify the molecular events by which L-arginine promotes muscle membrane integrity in dystrophic muscle and suggest that NF-B-related signaling cascades could be potential therapeutic targets for DMD management.