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Therefore, this study aims to investigate the mechanisms underlying the pathogenesis and progression of SO. We utilized natural aging mice fed high-fat diets (HFD) to simulate the progression of muscle mass decline observed in geriatric populations and high-calorie diets prevalent in modern societies, creating an SO animal model with exceptional clinical relevance. Our study demonstrates that HFD exacerbates age-related reductions in muscle mass, accompanied by decreased physical performance and increased lipid accumulation. Importantly, HFD-induced lipid infiltration emerges as a significant contributor to the further decline in skeletal muscle mass in SO mice, and the Nrf2\/Prdx6 pathway is a mechanism regulating this factor. Aerobic exercise, a safe and reliable means for older adults, is particularly effective for fat loss and muscle maintenance. In our study, aerobic exercise effectively alleviated the detrimental effects of HFD on muscle health in aging mice. Mechanistic studies revealed that Nrf2 and Prdx6 protein expression was significantly suppressed in vivo by HFD and in vitro following palmitic acid (PA) exposure. Conversely, overexpression of Nrf2 and Prdx6 in vitro was able to mimic the protective effects of aerobic exercise. Our results indicate that the Nrf2\/Prdx6 pathway plays a crucial role in counteracting muscle mass loss induced by HFD and may underlie beneficial effects of aerobic exercise on skeletal muscle.<\/jats:p>","DOI":"10.1093\/gerona\/glaf271","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T13:14:36Z","timestamp":1765372476000},"source":"Crossref","is-referenced-by-count":3,"title":["High-fat diet exacerbates skeletal muscle mass loss via Nrf2\/Prdx6 pathway in sarcopenic obesity mice"],"prefix":"10.1093","volume":"81","author":[{"given":"Danni","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Medical Technology, School of Rehabilitation Medicine, Tianjin Medical University , Tianjin,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Medical Technology, School of Rehabilitation Medicine, Tianjin Medical 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