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.
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This work was sponsored by Shanghai Pujiang Program (17PJD021), the interdisciplinary program of Shanghai Jiao Tong University (YG2017MS07), the distinguished Young Scholar of Ninth People’s Hospital (jyyq09201701), and the SHIPM-mu fund no. JC201805 from Shanghai Institute of Precision Medicine, Ninth People’s Hospital Shanghai affiliated to Jiao Tong University School of Medicine.
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Liu, Y., Bi, X., Zhang, Y. et al. Mitochondrial dysfunction/NLRP3 inflammasome axis contributes to angiotensin II-induced skeletal muscle wasting via PPAR-γ. Lab Invest (2019). https://doi.org/10.1038/s41374-019-0355-1