Transcriptomic Insights into Aerobic Exercise-Mediated Attenuation of High-Fat Diet–Induced Muscle Wasting

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 ß-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. Overall design: After 1 week of acclimation, 3-week-old male C57BL/6J mice were randomly allocated to four groups: standard chow diet (C), standard chow diet plus MICT (CM), HFD (H), and HFD plus MICT (HM). The dietary intervention was maintained throughout the entire experiment (weeks 1–21). Starting at week 13, mice assigned to the exercise groups completed a 1-week treadmill acclimation phase (10 m/min for 10 min/day, 5 days/week), followed by an 8-week MICT intervention (weeks 14–21). Each session lasted 45 min and was performed 5 days per week, preceded by a 10-min warm-up at 10 m/min. Treadmill speed was progressively increased from 13 m/min (weeks 14–15) to 15 m/min (weeks 16–17), and then to 17 m/min (weeks 18–21). Gastrocnemius muscles were collected for RNA-seq at the endpoint.