L-arginine decreases inflammation and modulates the nuclear factor-κB/matrix metalloproteinase cascade in mdx muscle fibers
L-arginine decreases inflammation and modulates the nuclear factor-κB/matrix metalloproteinase cascade in mdx muscle fibers
复制标题
DOI：
10.2353/ajpath.2008.071009
复制
发表时间：
2008-06-01
影响因子：
6
通讯作者：
Mornet, Dominique
中科院分区：
文献类型：
--
作者：
Hnia, Karim;Gayraud, Jerome;Mornet, Dominique
杜氏肌营养不良症 (DMD) 是一种致命的 X 连锁疾病，与肌营养不良蛋白缺乏相关，可导致慢性炎症、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-精氨酸作为药物治疗来减轻 DMD 的营养不良模式。然而，人们对 L-精氨酸治疗后营养不良性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，我们询问 L-精氨酸是否抑制炎症信号级联反应。我们证明 L-精氨酸可以减少 mdx 小鼠模型中的炎症并增强肌肉再生。 mdx 小鼠肌肉中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 -a 等经典刺激信号显着减少，导致核因子 (NF)-κ B 水平和活性降低。 NF-kappa B 作为关键转录因子，具有多级调控；先前的研究表明 mdx 和 DMD 肌肉中 NF-kappa B 信号传导受到干扰。此外，L-精氨酸降低金属蛋白酶 (MMP)-2 和 MMP-9 的活性，而金属蛋白酶 (MMP)-2 和 MMP-9 是由 NF-kappa B 转录激活的。我们发现，L-精氨酸对 NF-kappa B/MMP 级联的抑制作用减少了 β-肌营养不良聚糖的裂解，并使肌营养不良蛋白和 nNOS 在整个肌膜中易位。总的来说，我们的结果阐明了 L-精氨酸促进营养不良性肌肉中肌膜完整性的分子事件，并表明 NF-kappa B 相关信号级联可能是 DMD 管理的潜在治疗靶点。
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-1 beta, interieukin-6, and tumor necrosis factor-a, are significantly decreased in mdx mouse muscle, resulting in lower nuclear factor (NF)-kappa B levels and activity. NF-kappa B serves as a pivotal transcription factor with multiple levels of regulation; previous studies have shown perturbation of NF-kappa 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-kappa B. We show that the inhibitory effect of L-arginine on the NF-kappa B/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-kappa B-related signaling cascades could be potential therapeutic targets for DMD management.