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

Abstract

Duchenne muscular dystrophy (DMD) is a lethal, Xlinked 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-1␤, 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 ␤-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. (Am J Pathol

Inflammatory and alternatively activated human macrophages attract vessel-associated stem cells, relying on separate HMGB1- and MMP-9-dependent pathways

“…NO exerts pleiotropic effects in peripheral tissues [37]. In particular, it has beneficial effects in muscle repair and regeneration, mediating active suppression of proinflammatory signals such as IL-1, IL-6, and TNF-␣ [38]. Accordingly, mesoangioblast treatment with NO-releasing drugs facilitates their localization into dystrophic muscles after intrafemoral artery injection and their differentiation into functional muscle fibers [39,40].…”

Peptide-Based Inhibition of NF-κB Rescues Diaphragm Muscle Contractile Dysfunction in a Murine Model of Duchenne Muscular Dystrophy

“…In addition to NBD, other anti-NF-κB pharmacological and biological agents (5,(15)(16)(17)(18)(19)(20)(21) have been shown to be efficacious in rescuing mdx pathology to varying degrees. However, unknown at this point is whether any of these agents are suitable for development into clinically useable drugs.…”

Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle

“…Mtm1-KO and control male mice were euthanized by rapid cervical dislocation. Muscles were rapidly isolated and treated as described previously (45). Human biopsies were obtained in accordance with the French and European legislations following the written consent of all patients and control subjects.…”