Differential effects of aerobic, resistance, and combined exercise on skeletal muscle function in high-fat diet-induced obese mice: integration of gut microbiota and metabolomics.

OBJECTIVE

This study tested the hypothesis that aerobic, resistance, and combined exercise differentially remodel gut microbiota composition and serum metabolic profiles, and that these modifications are associated with modality-specific improvements in skeletal muscle function and morphology through the gut-muscle axis in high-fat diet-induced obese mice.

METHODS

Six-week-old male C57BL/6J mice were randomly assigned to a control group (C, standard diet), a high-fat diet group (HF), and high-fat diet groups subjected to aerobic exercise (HFA), resistance exercise (HFR), or combined exercise (HFAR). Exercise interventions were conducted for 8 weeks. Following the intervention, skeletal muscle endurance and strength were assessed. Tibialis anterior muscles were harvested for hematoxylin-eosin, Oil Red O, Picro-Sirius Red, and succinate dehydrogenase staining. Mitochondrial DNA (mtDNA) copy number was quantified as a marker of mitochondrial biogenesis. Gut microbiota composition was analyzed by 16S rRNA gene sequencing, and serum metabolites were profiled using untargeted liquid chromatography-mass spectrometry metabolomics.

RESULTS

Compared with the HF group, all exercise groups showed improvements in treadmill endurance and relative grip strength, along with amelioration of the pathological morphological alterations observed in skeletal muscle, including reduced lipid accumulation and fibrosis. The HFAR exhibited the most pronounced effects, including improved muscle fiber morphology, an increased proportion of slow-twitch fibers, elevated mtDNA content, and reduced lipid deposition and fibrosis. Gut microbiota analysis demonstrated significantly reduced α-diversity in the HF group compared to the C group, whereas the HFAR group presented the most substantial restoration of diversity. β-diversity analysis indicated that exercise interventions shifted gut microbiota composition toward that of the control group. Linear discriminant analysis effect size analysis identified exercise modality-specific microbial changes, including enrichment of Blautia in the HFR group and Romboutsia in the HFAR group. Metabolomic analysis identified 278 differential metabolites, with distinct regulatory patterns across metabolic pathways depending on exercise modality. Correlation analysis demonstrated significant associations between specific bacterial genera and differential metabolites.

CONCLUSIONS

Aerobic, resistance, and combined exercise differentially ameliorated skeletal muscle dysfunction in high-fat diet-induced obese mice. These effects were associated with modality-specific changes in gut microbiota composition and host metabolic profiles.