Zujie Xu , Zheying Ma , Huiqian Ren , Yaming Yang , Xiaoqin Zhao , Shou Pan , Jie Tang , Bing Zhang
{"title":"运动训练通过下调STING来改善高脂饮食诱导的骨骼肌萎缩和铁下垂","authors":"Zujie Xu , Zheying Ma , Huiqian Ren , Yaming Yang , Xiaoqin Zhao , Shou Pan , Jie Tang , Bing Zhang","doi":"10.1016/j.freeradbiomed.2025.08.043","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>High-fat diet (HFD)-induced sarcopenic obesity can lead to reductions in muscle fiber diameter, enhanced protein degradation, and various forms of cell death. Exercise training has been shown to alleviate HFD-induced muscle atrophy. However, the underlying mechanism remains unclear. Stimulator of interferon genes (STING) is involved in ferroptosis and various forms of muscle atrophy. This study aimed to investigate the role of STING in exercise training against HFD-induced skeletal muscle atrophy.</div></div><div><h3>Methods</h3><div>In vivo, HFD-fed mice were subjected to exercise training and were intraperitoneally injected with the STING agonist diABZI or selective STING inhibitor C-176 for 8 weeks. In vitro, the differentiated C2C12 myotubes were treated with palmitic acid (PA), followed by interventions with Ferrostatin-1 (Fer-1), Erastin, diABZI or C-176. Grip strength test, body composition analysis, serum assay, histology analysis, dihydroethidium staining, transmission electron microscopy, myosin heavy chain staining, mitochondrial membrane potential, Western blot, and real-time quantitative PCR were performed.</div></div><div><h3>Results</h3><div>In vivo, exercise training significantly reduced the mRNA and protein expression of STING and ameliorated skeletal muscle atrophy and lipid peroxidation associated ferroptosis in HFD-fed mice. The STING agonist diABZI blunted the alleviative effect of exercise training in HFD-induced skeletal muscle atrophy and ferroptosis. The selective STING inhibitor C-176 and exercise training synergistically alleviated HFD-induced skeletal muscle atrophy and ferroptosis. In vitro, the ferroptosis inhibitor Fer-1 partially rescued PA-triggered C2C12 myotubes atrophy and ferroptosis, whereas the ferroptosis activator Erastin aggravated myotubes atrophy and ferroptosis. diABZI exacerbated PA-induced C2C12 myotubes atrophy and ferroptosis. Erastin impaired the ameliorative effect of C-176 in PA-induced C2C12 myotubes atrophy and ferroptosis.</div></div><div><h3>Conclusions</h3><div>Exercise training effectively suppressed HFD-mediated upregulation of STING in skeletal muscle. STING is a response factor for the alleviative effect of exercise training in HFD-induced skeletal muscle atrophy and ferroptosis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 373-383"},"PeriodicalIF":8.2000,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exercise training ameliorates high-fat diet-induced skeletal muscle atrophy and ferroptosis via downregulation of STING\",\"authors\":\"Zujie Xu , Zheying Ma , Huiqian Ren , Yaming Yang , Xiaoqin Zhao , Shou Pan , Jie Tang , Bing Zhang\",\"doi\":\"10.1016/j.freeradbiomed.2025.08.043\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>High-fat diet (HFD)-induced sarcopenic obesity can lead to reductions in muscle fiber diameter, enhanced protein degradation, and various forms of cell death. Exercise training has been shown to alleviate HFD-induced muscle atrophy. However, the underlying mechanism remains unclear. Stimulator of interferon genes (STING) is involved in ferroptosis and various forms of muscle atrophy. This study aimed to investigate the role of STING in exercise training against HFD-induced skeletal muscle atrophy.</div></div><div><h3>Methods</h3><div>In vivo, HFD-fed mice were subjected to exercise training and were intraperitoneally injected with the STING agonist diABZI or selective STING inhibitor C-176 for 8 weeks. In vitro, the differentiated C2C12 myotubes were treated with palmitic acid (PA), followed by interventions with Ferrostatin-1 (Fer-1), Erastin, diABZI or C-176. Grip strength test, body composition analysis, serum assay, histology analysis, dihydroethidium staining, transmission electron microscopy, myosin heavy chain staining, mitochondrial membrane potential, Western blot, and real-time quantitative PCR were performed.</div></div><div><h3>Results</h3><div>In vivo, exercise training significantly reduced the mRNA and protein expression of STING and ameliorated skeletal muscle atrophy and lipid peroxidation associated ferroptosis in HFD-fed mice. The STING agonist diABZI blunted the alleviative effect of exercise training in HFD-induced skeletal muscle atrophy and ferroptosis. The selective STING inhibitor C-176 and exercise training synergistically alleviated HFD-induced skeletal muscle atrophy and ferroptosis. In vitro, the ferroptosis inhibitor Fer-1 partially rescued PA-triggered C2C12 myotubes atrophy and ferroptosis, whereas the ferroptosis activator Erastin aggravated myotubes atrophy and ferroptosis. diABZI exacerbated PA-induced C2C12 myotubes atrophy and ferroptosis. Erastin impaired the ameliorative effect of C-176 in PA-induced C2C12 myotubes atrophy and ferroptosis.</div></div><div><h3>Conclusions</h3><div>Exercise training effectively suppressed HFD-mediated upregulation of STING in skeletal muscle. STING is a response factor for the alleviative effect of exercise training in HFD-induced skeletal muscle atrophy and ferroptosis.</div></div>\",\"PeriodicalId\":12407,\"journal\":{\"name\":\"Free Radical Biology and Medicine\",\"volume\":\"240 \",\"pages\":\"Pages 373-383\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2025-08-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Free Radical Biology and Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0891584925009311\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Free Radical Biology and Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0891584925009311","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Exercise training ameliorates high-fat diet-induced skeletal muscle atrophy and ferroptosis via downregulation of STING
Background
High-fat diet (HFD)-induced sarcopenic obesity can lead to reductions in muscle fiber diameter, enhanced protein degradation, and various forms of cell death. Exercise training has been shown to alleviate HFD-induced muscle atrophy. However, the underlying mechanism remains unclear. Stimulator of interferon genes (STING) is involved in ferroptosis and various forms of muscle atrophy. This study aimed to investigate the role of STING in exercise training against HFD-induced skeletal muscle atrophy.
Methods
In vivo, HFD-fed mice were subjected to exercise training and were intraperitoneally injected with the STING agonist diABZI or selective STING inhibitor C-176 for 8 weeks. In vitro, the differentiated C2C12 myotubes were treated with palmitic acid (PA), followed by interventions with Ferrostatin-1 (Fer-1), Erastin, diABZI or C-176. Grip strength test, body composition analysis, serum assay, histology analysis, dihydroethidium staining, transmission electron microscopy, myosin heavy chain staining, mitochondrial membrane potential, Western blot, and real-time quantitative PCR were performed.
Results
In vivo, exercise training significantly reduced the mRNA and protein expression of STING and ameliorated skeletal muscle atrophy and lipid peroxidation associated ferroptosis in HFD-fed mice. The STING agonist diABZI blunted the alleviative effect of exercise training in HFD-induced skeletal muscle atrophy and ferroptosis. The selective STING inhibitor C-176 and exercise training synergistically alleviated HFD-induced skeletal muscle atrophy and ferroptosis. In vitro, the ferroptosis inhibitor Fer-1 partially rescued PA-triggered C2C12 myotubes atrophy and ferroptosis, whereas the ferroptosis activator Erastin aggravated myotubes atrophy and ferroptosis. diABZI exacerbated PA-induced C2C12 myotubes atrophy and ferroptosis. Erastin impaired the ameliorative effect of C-176 in PA-induced C2C12 myotubes atrophy and ferroptosis.
Conclusions
Exercise training effectively suppressed HFD-mediated upregulation of STING in skeletal muscle. STING is a response factor for the alleviative effect of exercise training in HFD-induced skeletal muscle atrophy and ferroptosis.
期刊介绍:
Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.