Exercise training attenuates high-fat diet-induced skeletal muscle atrophy by inhibiting Drp1-mediated cuproptosis in male mice.
Hu M, Yuan Y, An Z, Wang J, Li X, Liu X et al. · Cellular signalling · 2026
Objective: The present study investigated the role of Drp1 in cuproptosis and its underlying mechanisms, while examining the effects of aerobic exercise on high-fat diet-induced skeletal muscle atrophy. These
Findings: may provide a theoretical basis for exercise interventions and targeted therapies for obesity-associated skeletal muscle atrophy.
Methods: Five-week-old male C57BL/6J mice (n = 10 per group) were randomly assigned to a normal diet (ND) or high-fat diet (HFD) and subsequently subjected to aerobic exercise or Mdivi-1 intervention for 8 weeks. Body composition, skeletal muscle mass, grip strength, and endurance capacity were evaluated. Muscle morphology, mitochondrial function, oxidative stress, and copper homeostasis were assessed using H&E staining, JC-1 staining, DHE staining, biochemical assays, and copper measurements. Muscle atrophy proteins, Drp1, and cuproptosis markers were assessed at protein and mRNA levels by Western blotting, immunofluorescence, and RT-qPCR. Differences among multiple groups were analyzed using two-way ANOVA, whereas differences between two groups were analyzed using Student's unpaired t-test.
Results: HFD induced skeletal muscle atrophy, as evidenced by reduced muscle mass, grip strength, and endurance capacity. This was accompanied by mitochondrial dysfunction, oxidative stress, and increased expression of Drp1 and cuproptosis-related markers. Aerobic exercise significantly ameliorated these pathological changes. Similar protective effects were observed following pharmacological inhibition of Drp1 with Mdivi-1.
Conclusions: Aerobic exercise alleviates HFD-induced skeletal muscle atrophy by suppressing Drp1 expression, thereby reducing copper accumulation and cuproptosis in skeletal muscle.