Huang Tian-Jin, Shang Shu, Wan Qin, Li Qiang, Li Yang-Jingsi, Zheng Jin-Na, Chen Fa-Xiu
Department of Geriatrics, Jiangxi Provincial People's Hospital, No. 92 Aiguo Rd, Donghu District, Nanchang, Jiangxi, 330006, China.
Department of Geriatrics, The First Affiliated Hospital of Nanchang Medical College, No. 92 Aiguo Rd, Donghu District, Nanchang, Jiangxi, 330006, China.
Cell Mol Life Sci. 2025 Apr 7;82(1):142. doi: 10.1007/s00018-025-05657-1.
Sarcopenia, the age-related decline in muscle mass and function, poses a major health risk to the elderly population. Although dietary advanced glycation end-products (AGEs) have been implicated in worsening sarcopenia, the precise molecular mechanisms remain unclear.
A sarcopenia animal model was established by feeding a high AGE diet to C57BL/6 mice. Muscle function and mass were assessed using grip strength tests, and rotarod tests. Proteomic analysis was used to identify differentially expressed proteins. Immunoprecipitation, mass spectrometry, and co-immunoprecipitation were employed to investigate protein interactions both in vivo and in vitro. Quantitative reverse transcription PCR and Western blotting were conducted to measure gene and protein expression levels.
Our results revealed that dietary AGEs accelerated the onset of sarcopenia in mice by triggering apoptosis. Proteomic analysis showed a marked upregulation of protein arginine methyltransferase 1 (PRMT1) in the muscle tissues of mice fed a high AGE diet. PRMT1 mediated the arginine methylation of CREB-regulated transcription coactivator 3 (CRTC3) at the R534 site within its transactivation domain, leading to CRTC3 activation. The activated CRTC3, together with Forkhead box O3a (FOXO3a), transactivated the BAX (BCL2 associated X) gene, initiating Bax downstream signaling, promoting apoptosis in muscle cells, and contributing to muscle atrophy. Inhibition of PRMT1 prevented CRTC3 methylation and suppressed Bax-mediated apoptotic signaling in vitro. Moreover, in vivo treatment with PRMT1 and Bax inhibitors significantly attenuated AGE-induced sarcopenia in mice.
PRMT1-mediated CRTC3 arginine methylation plays a critical role in AGE-induced sarcopenia and suggests potential therapeutic targets for preventing sarcopenia progression.
肌肉减少症是与年龄相关的肌肉质量和功能下降，对老年人群构成重大健康风险。尽管膳食晚期糖基化终产物（AGEs）被认为会加重肌肉减少症，但其确切分子机制仍不清楚。
通过给C57BL/6小鼠喂食高AGE饮食建立肌肉减少症动物模型。使用握力测试和转棒试验评估肌肉功能和质量。蛋白质组学分析用于鉴定差异表达的蛋白质。采用免疫沉淀、质谱和免疫共沉淀技术研究体内和体外的蛋白质相互作用。进行定量逆转录PCR和蛋白质免疫印迹法以测量基因和蛋白质表达水平。
我们的结果表明，膳食AGEs通过触发细胞凋亡加速了小鼠肌肉减少症的发生。蛋白质组学分析显示，喂食高AGE饮食的小鼠肌肉组织中蛋白质精氨酸甲基转移酶1（PRMT1）显著上调。PRMT1介导CREB调节的转录共激活因子3（CRTC3）在其反式激活域内R534位点的精氨酸甲基化，导致CRTC3激活。激活的CRTC3与叉头框O3a（FOXO3a）一起反式激活BAX（BCL2相关X）基因，启动Bax下游信号传导，促进肌肉细胞凋亡，并导致肌肉萎缩。抑制PRMT1可防止CRTC3甲基化，并在体外抑制Bax介导的凋亡信号传导。此外，在体内用PRMT1和Bax抑制剂治疗可显著减轻AGE诱导的小鼠肌肉减少症。
PRMT1介导的CRTC3精氨酸甲基化在AGE诱导的肌肉减少症中起关键作用，并提示了预防肌肉减少症进展的潜在治疗靶点。
