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Mitochondrial dysfunction/NLRP3 inflammasome axis contributes to angiotensin II-induced skeletal muscle wasting via PPAR-γ.
Laboratory Investigation ( IF 5 ) Pub Date : 2019-12-19 , DOI: 10.1038/s41374-019-0355-1
Yuqing Liu 1 , Xiao Bi 1 , Yumei Zhang 1 , Yingdeng Wang 1 , Wei Ding 1
Affiliation  

Angiotensin II (Ang II) levels are elevated in patients with chronic kidney disease or heart failure, and directly causes skeletal muscle wasting in rodents, but the molecular mechanisms of Ang II-induced skeletal muscle wasting and its potential as a therapeutic target are unknown. We investigated the NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated muscle atrophy response to Ang II in C2C12 myotubes and Nlrp3 knockout mice. We also assessed the mitochondrial dysfunction (MtD)/NLRP3 inflammasome axis in Ang II-induced C2C12 myotubes. Finally, we examined whether a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist could attenuate skeletal muscle wasting by targeting the MtD/NLRP3 inflammasome axis in vitro and in vivo. We demonstrated that Ang II increased NLRP3 inflammasome activation in cultured C2C12 myotubes dose dependently. Nlrp3 knockdown or Nlrp3-/- mice were protected from the imbalance of protein synthesis and degradation. Exposure of C2C12 to Ang II increased mitochondrial ROS (mtROS) generation, accompanied by MtD. Remarkably, the mitochondrial-targeted antioxidant not only decreased mtROS and MtD, it also significantly inhibited NLRP3 inflammasome activation and restored skeletal muscle atrophy. Finally, the PPAR-γ agonist protected against Ang II-induced muscle wasting by preventing MtD, oxidative stress, and NLRP3 inflammasome activation in vitro and in vivo. This work suggests a potential role of MtD/NLRP3 inflammasome pathway in the pathogenesis of Ang II-induced skeletal muscle wasting, and targeting the PPAR-γ/MtD/NLRP3 inflammasome axis may provide a therapeutic approach for muscle wasting.

中文翻译:

线粒体功能障碍/NLRP3 炎性体轴通过 PPAR-γ 促进血管紧张素 II 诱导的骨骼肌萎缩。

慢性肾病或心力衰竭患者的血管紧张素 II (Ang II) 水平升高,并直接导致啮齿动物骨骼肌萎缩,但 Ang II 诱导骨骼肌萎缩的分子机制及其作为治疗靶点的潜力尚不清楚。我们在 C2C12 肌管和 Nlrp3 敲除小鼠中研究了含有 3 (NLRP3) 炎症小体介导的对 Ang II 的肌肉萎缩反应的 NLR 家族热蛋白结构域。我们还评估了 Ang II 诱导的 C2C12 肌管中的线粒体功能障碍 (MtD)/NLRP3 炎性体轴。最后,我们检查了过氧化物酶体增殖物激活受体-γ (PPAR-γ) 激动剂是否可以通过在体外和体内靶向 MtD/NLRP3 炎性体轴来减轻骨骼肌消耗。我们证明了 Ang II 剂量依赖性地增加了培养的 C2C12 肌管中 NLRP3 炎性体的激活。Nlrp3 敲低或 Nlrp3-/- 小鼠免受蛋白质合成和降解失衡的影响。C2C12 暴露于 Ang II 会增加线粒体 ROS (mtROS) 的生成,并伴有 MtD。值得注意的是,靶向线粒体的抗氧化剂不仅降低了 mtROS 和 MtD,还显着抑制了 NLRP3 炎性体激活并恢复了骨骼肌萎缩。最后,PPAR-γ 激动剂通过在体外和体内预防 MtD、氧化应激和 NLRP3 炎性体激活来防止 Ang II 诱导的肌肉萎缩。这项工作表明 MtD/NLRP3 炎性体通路在 Ang II 诱导的骨骼肌萎缩的发病机制中的潜在作用,
更新日期:2019-12-19
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