<i>trans</i>-Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction

Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of <i>trans</i>-resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity. Additionally, inflammatory balance was restored via suppression of pro-inflammatory IL-6 and elevation of anti-inflammatory IL-10 levels. These findings highlight the synergistic benefits of combining polyphenol supplementation with aerobic exercise as a promising strategy for mitigating muscle atrophy under metabolic stress conditions.