Objective: To compare the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on glucose metabolism in skeletal muscle of T2DM mice, and to investigate the potential regulatory mechanisms of MSTN/AMPK/PGC-1α signaling on mitochondrial quality control and its relationship with glucose metabolism.
Methods: Potential molecular targets for exercise intervention in glucose metabolism of T2DM patients were identified using bioinformatics analysis, followed by validation through animal experiments. Eight-week-old male db/db mice were randomly divided into a diabetic control group (DC group), a moderate-intensity continuous training group (MICT group), and a high-intensity interval training group (HIIT group). Age-matched db/m mice served as the normal control group (NC group), with 12 mice in each group. The NC and DC groups did not undergo exercise, while the MICT and HIIT groups underwent 10 weeks of MICT and HIIT, respectively. Skeletal muscle glucose metabolism, myofiber structure, mitochondrial quality, and protein expression were assessed using staining, transmission electron microscopy, enzyme activity tests, qRT-PCR, and Western blotting.
Results: Bioinformatics analysis suggested that MSTN might be a key driver in the improvement of glucose metabolism in T2DM through exercise intervention. Animal experiment results showed that compared to the NC group, the DC group had significantly higher body weight, random blood glucose, and L-LDH enzyme activity (P < 0.001), while GLUT4 protein expression and G6PDH enzyme activity were significantly lower (P < 0.01 or P < 0.001). The MICT and HIIT groups had significantly lower body weight, random blood glucose, and L-LDH enzyme activity than the DC group (P < 0.05 or P < 0.01), and significantly higher GLUT4 protein expression and G6PDH enzyme activity (P < 0.001). The cross-sectional area of skeletal muscle, glycogen content, GLUT4 protein expression, and G6PDH enzyme activity were significantly higher in the HIIT group than in the MICT group (P < 0.05 or P < 0.001), while L-LDH enzyme activity was significantly lower in the HIIT group than in the MICT group (P < 0.001). Compared to the NC group, the DC group had sparse and disordered myofibers, sparse and unevenly distributed glycogen granules, smaller mitochondria with cristae disruption, membrane damage, and partial vacuolization, with significant reductions in myofiber cross-sectional area and glycogen content (P < 0.001). The MICT and HIIT groups had increased myofiber density and improved mitochondrial cristae disruption and membrane damage, with mitochondrial fission and fusion occurring, and significant increases in myofiber cross-sectional area and glycogen content (P < 0.05 or P < 0.001). The mtDNA copy number, NRF2, TFAM, OPA1, MFN2, DRP1, PINK1, PARKIN, AMPK, P-AMPK, and PGC-1α protein expressions were significantly lower in the DC group than in the NC group (P < 0.01 or P < 0.001), and significantly higher in the MICT and HIIT groups than in the DC group (P < 0.01 or P < 0.001). Except for MFN2, all these indicators were significantly higher in the HIIT group than in the MICT group (P < 0.05 or P < 0.01 or P < 0.001). The MSTN protein expression was significantly higher in the DC group than in the NC group (P < 0.01), and significantly lower in the MICT and HIIT groups than in the DC group (P < 0.001).
Conclusion: Both HIIT and MICT improve glucose metabolic disorders in the skeletal muscle of T2DM mice by downregulating MSTN expression, activating the AMPK/PGC-1α signaling pathway, and enhancing mitochondrial quality control. The intervention effect of HIIT is superior to that of MICT.
