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.