Mechanistic Study of Maternal Exercise Mitigatinging High-Fat Diet Induced Skeletal Muscle Dysfunction in Offspring Mice

Objective: To investigate the protective effects and underlying mechanisms of maternal exercise on skeletal muscle dysfunction induced by long-term high-fat diet(HFD) in offspring mice. Methods: Female C57BL/6 mice were randomly divided into maternal con group(M-Con) and maternal exercise group(M-Ex). The M-Ex group underwent treadmill exercise for 4 weeks before and during pregnancy, while the M-Con group maintained a regular lifestyle. Both groups were kept in the same environment during the training period. Offspring mice were obtained by mating M-Con and the M-Ex females with age-matched wild-type C57BL/6 males. After normal rearing until 3 weeks of age, the offspring were subjected to a 12-week HFD intervention. Skeletal muscle function in offspring was assessed by exercise performance tests, and the cross-sectional area(CSA), lipid deposition,fibrosis and fiber type of skeletal muscle fibers were analyzed by histochemical staining. The protein expression of mTOR, P70s6k,Fbx32, TNF-α, TNFR1, AMPK and PGC-1α in skeletal muscle was detected by Western blot, and the expression of genes related to lipid synthesis and mitochondrial biogenesis was detected by RT-PCR. Results: Compared to wild-type mice with normal diet(Sham), offspring from the M-Con group(HFD.Con) showed significantly reduced exercise performance, decreased skeletal muscle index and fiber CSA, increased expression of lipid synthesis-related genes, elevated ectopic lipid deposition and fibrosis in skeletal muscle, and higher plasma TNF-α level after long-term HFD. Moreover, skeletal muscle TNF-α and TNFR1 protein levels were upregulated, the mitochondrial function was impaired, the number of SDH-stained positive fibers was reduced, and AMPK and PGC-1α protein expression level were significantly downregulated. Compared with the HFD.Con group, offspring mice(HFD.Ex) from the M-Ex group showed significantly increased expression of AMPK and PGC-1α proteins in skeletal muscle, along with higher levels of mitochondrial biogenesis-related genes and SDH-staining positive fibers. Additionally, the expression of lipid synthesisrelated genes and TNF-α and TNFR1 proteins was significantly downregulated, reducing lipid deposition and fibrosis, thereby resisting skeletal muscle dysfunction caused by a long-term high-fat diet. Conclusions: Maternal exercise actives AMPK/PGC-1αsignaling pathway in offspring skeletal muscle, promoting mitochondrial biogenesis, reducing obesity and ectopic lipid deposition induced by long-term HFD, and inhibiting serum TNF-α levels and skeletal muscle TNFR1 protein expression. These effects effectively alleviate muscle atrophy and fibrosis in offspring, protecting skeletal muscle against metabolic dysfunction.