ABSTRACT: Chronic consumption of high-fat diet (HFD) induces obesity and metabolic dysfunction and is accompanied by progressive skeletal muscle wasting. Although aerobic exercise is generally considered less effective for maintaining muscle mass, accumulating evidence suggests that it can attenuate HFD-induced muscle wasting. However, the molecular mechanisms underlying this protective effect remain poorly defined. In this study, we investigated the effects of moderate-intensity continuous training (MICT) on HFD-induced muscle wasting and characterized the associated transcriptomic adaptations in the mouse gastrocnemius muscle. Twenty-one weeks of HFD feeding increased body weight and serum glucose levels and induced marked muscle wasting, as evidenced by reduced gastrocnemius muscle index, impaired normalized forelimb grip strength, decreased muscle fiber cross-sectional area, and excessive intramuscular lipid accumulation. These pathological alterations were significantly attenuated by an 8-week MICT intervention. RNA sequencing revealed that HFD predominantly induced a lipid-centered transcriptional program characterized by enhanced fatty acid uptake, trafficking, and β-oxidation. In contrast, MICT predominantly suppressed atrophy-associated genes (Foxo1, Fbxo32, and Trim63), while exerting minimal effects on myogenic genes (Pax7, Myod1, and Myog). Functional enrichment analyses further indicated that MICT modulated signaling pathways related to FoxO, PI3K–Akt, MAPK, and insulin signaling, together with biological processes associated with angiogenesis and calcium signaling. Collectively, these results suggest that MICT mitigates HFD-induced muscle wasting primarily by reprogramming the transcriptome from a lipotoxic, atrophic state toward a more insulin-sensitive, pro-angiogenic profile, with limited myogenic activation.
