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The Regulatory Role of the SIRT1/Foxo1 Pathway in the Prevention of Insulin Resistance in Skeletal Muscle by Aerobic Exercise in Mice

Haitao Wang, Wenqian Yang, Guang Yang6, Yuqian Liu*

Silent Information Regulator Proteins (SIRT) plays key roles in glucose and lipid metabolism and homeostasis. The SIRT1 inhibitor was used to investigate the mechanism of the SIRT1/FoxO1 (Forkhead box O1) pathway in mice and its function in the prevention of insulin resistance in skeletal muscle. Forty male mice were randomly divided into a control group and three experimental groups (NH: High-fat diet, HE: High-fat diet plus exercise, and HES: High-fat diet plus exercise and SIRT1 inhibitor). After 14 weeks, the fat weight, blood glucose level, and HOMA-IR score in HES were significantly increased compared to those in HE (P<0.01). The same parameters were significantly decreased in HE compared to those in the NH group (P<0.01). Mitochondrial 8-OHdG (8-hydroxy-2 deoxyguanosine) level of the HES group was significantly higher than that of the HE group (P<0.01). Compared with NH, the 8-OHdG and 4-HNE (4-hydroxynonenal) level were significantly decreased in HE (P<0.01). Histologic evaluation demonstrated mitochondrial vacuoles in HES, while a clean arrangement of mitochondrial cristae was observed in HE. FoxO1 acetylation was enhanced in HES compared to that in HE (P<0.01). The insulin resistance was induced in mice after 14-week high-fat diet, while glucose metabolism was significantly improved by aerobic exercise. The physiologic adaptations induced by exercise were not observed in the presence of an SIRT1 inhibitor. Thus, the SIRT1/FoxO1 pathway effectively regulates glucose metabolism during aerobic exercise and also prevents fat-induced peroxidation injury in skeletal muscles.