Xie Ting, Qiao Xinhua, Sun Chuanxin, Chu Boyu, Meng Jiao, Chen Chang
School of Basic Medical Sciences of Southwest Medical University, Luzhou, 646000, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Nitric Oxide. 2022 Mar 1;120:1-8. doi: 10.1016/j.niox.2021.12.006. Epub 2021 Dec 29.
The age-related loss of muscle mass and muscle function known as sarcopenia is a major public health problem among older people. Recent research suggests that activation of apoptotic signaling is a critical aspect of the pathogenesis of age-related sarcopenia. However, little information exists in the literature about the apoptotic mechanism of sarcopenia in aging. Herein, we report that elevated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) S-nitrosation and apoptosis occur in sarcopenia during natural aging and that translocation of S-nitrosated GAPDH to the nucleus and S-nitrosated GAPDH-mediated apoptosis contributed to sarcopenia. The levels and sites of GAPDH S-nitrosation in muscle tissues of young, adult and old mice were studied with a quantitative S-nitrosation proteomic analysis approach. GAPDH S-nitrosation increased with aging, and the GAPDH modification sites Cys, Cys and Cys were identified. The upregulated S-nitrosation of GAPDH relies on inducible nitric oxide synthase (iNOS) rather than enzymes involved in denitrosylation. Treatment with the iNOS inhibitor 1400W or mutation of GAPDH S-nitrosation sites alleviated apoptosis of C2C12 cells, further demonstrating that GAPDH S-nitrosation in aging contributes to sarcopenia. Taken together, these findings reveal a new cellular mechanism underlying age-related sarcopenia, and the demonstration of muscle loss mediated by iNOS-induced GAPDH S-nitrosation suggests a potential therapeutic strategy for sarcopenia.
与年龄相关的肌肉质量和肌肉功能丧失，即肌肉减少症，是老年人面临的一个主要公共卫生问题。最近的研究表明，凋亡信号的激活是年龄相关性肌肉减少症发病机制的一个关键方面。然而，文献中关于衰老过程中肌肉减少症的凋亡机制的信息很少。在此，我们报告在自然衰老过程中，肌肉减少症中甘油醛-3-磷酸脱氢酶（GAPDH）的S-亚硝基化水平升高和凋亡发生，并且S-亚硝基化的GAPDH易位至细胞核以及S-亚硝基化的GAPDH介导的凋亡导致了肌肉减少症。采用定量S-亚硝基化蛋白质组学分析方法研究了年轻、成年和老年小鼠肌肉组织中GAPDH的S-亚硝基化水平和位点。GAPDH的S-亚硝基化随着衰老而增加，并且鉴定出GAPDH的修饰位点Cys、Cys和Cys。GAPDH的S-亚硝基化上调依赖于诱导型一氧化氮合酶（iNOS），而不是参与去亚硝基化的酶。用iNOS抑制剂1400W处理或GAPDH S-亚硝基化位点突变可减轻C2C12细胞的凋亡，进一步证明衰老过程中GAPDH的S-亚硝基化导致了肌肉减少症。综上所述，这些发现揭示了年龄相关性肌肉减少症潜在的新细胞机制，并且由iNOS诱导的GAPDH S-亚硝基化介导的肌肉损失的证明提示了一种针对肌肉减少症的潜在治疗策略。
