Hnia Karim, Gayraud Jérôme, Hugon Gérald, Ramonatxo Michèle, De La Porte Sabine, Matecki Stefan, Mornet Dominique
INSERM ERI 25 Muscle et Pathologies, CHU A. de Villeneuve, Université de Montpellier1, EA 4202, 34295 Montpellier Cedex 5, France.
Am J Pathol. 2008 Jun;172(6):1509-19. doi: 10.2353/ajpath.2008.071009. Epub 2008 May 5.
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-1beta, interleukin-6, and tumor necrosis factor-alpha, are significantly decreased in mdx mouse muscle, resulting in lower nuclear factor (NF)-kappaB levels and activity. NF-kappaB serves as a pivotal transcription factor with multiple levels of regulation; previous studies have shown perturbation of NF-kappaB 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-kappaB. We show that the inhibitory effect of L-arginine on the NF-kappaB/MMP cascade reduces beta-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-kappaB-related signaling cascades could be potential therapeutic targets for DMD management.
杜兴氏肌营养不良症（DMD）是一种致命的X连锁疾病，与肌营养不良蛋白缺乏有关，会导致慢性炎症、肌膜损伤和严重的骨骼肌退化。最近，有人提出使用一氧化氮合酶（nNOS）的底物L-精氨酸作为一种药物治疗方法，以减轻DMD的营养不良模式。然而，对于L-精氨酸治疗的营养不良肌肉中发生的信号事件知之甚少。考虑到炎症在营养不良过程中的影响，我们研究了L-精氨酸是否抑制炎症信号级联反应。我们证明，L-精氨酸可减轻mdx小鼠模型中的炎症并增强肌肉再生。经典的刺激信号，如促炎细胞因子白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α，在mdx小鼠肌肉中显著降低，导致核因子（NF）-κB水平和活性降低。NF-κB是一种具有多种调节水平的关键转录因子；先前的研究表明，mdx和DMD肌肉中的NF-κB信号传导均受到干扰。此外，L-精氨酸降低了金属蛋白酶（MMP）-2和MMP-9的活性，这两种酶是由NF-κB转录激活的。我们表明，L-精氨酸对NF-κB/MMP级联反应的抑制作用减少了β-肌营养不良聚糖的裂解，并使抗肌萎缩蛋白和nNOS在整个肌膜上移位。总的来说，我们的结果阐明了L-精氨酸促进营养不良肌肉中肌膜完整性的分子事件，并表明NF-κB相关信号级联可能是DMD治疗的潜在靶点。
