Aerobic Exercise Attenuates High-Fat Diet-Induced Skeletal Muscle Atrophy by Suppressing Oxidative Stress, Inflammation, and Drp1-Associated Mitochondrial Fission.

High-fat diet (HFD)-induced skeletal muscle atrophy is characterized by impaired muscle mass and function, mitochondrial dysfunction, redox imbalance, and increased inflammation. Previous research has shown that aerobic exercise ameliorates HFD-induced skeletal muscle atrophy, but the underlying mechanisms remain unclear. Dynamin-related protein 1 (Drp1) is a key GTPase that mediates mitochondrial fission, maintains mitochondrial homeostasis, and regulates reactive oxygen species (ROS) production and inflammatory responses. This study investigated the potential involvement of Drp1-associated mitochondrial fission in the protective effects of aerobic exercise against HFD-induced skeletal muscle atrophy. HFD-fed mice underwent an 8-week aerobic exercise intervention, and Mdivi-1, a commonly used mitochondrial fission inhibitor, was administered intraperitoneally to further examine the involvement of mitochondrial fission. Assessments included grip strength, endurance testing, body composition, histology, transmission electron microscopy, immunofluorescence, DHE staining, antioxidant assays, Western blotting, and qPCR. Aerobic exercise reduced Drp1 phosphorylation, oxidative stress, and inflammatory responses in the skeletal muscle of HFD-fed mice and attenuated skeletal muscle atrophy. Mdivi-1 treatment produced similar protective effects, including attenuation of skeletal muscle atrophy, oxidative stress, and inflammatory responses. Together, these findings suggest that Drp1 phosphorylation and associated mitochondrial fission may contribute to the protective effects of aerobic exercise against HFD-induced skeletal muscle atrophy.