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Although exercise and nutritional interventions may alleviate disuse atrophy, their synergistic effects under microgravity conditions remain poorly characterized. This study investigated the effects of an 8-week ketogenic diet combined with aerobic exercise in hindlimb-unloaded mice on muscle fiber remodeling and metabolic adaptation. Methods: Seven-week-old male C57BL\/6J mice were randomly divided into six groups: normal diet control (NC), normal diet with hindlimb unloading (NH), normal diet with hindlimb unloading and exercise (NHE), ketogenic diet control (KC), ketogenic diet with hindlimb unloading (KH), and ketogenic diet with hindlimb unloading and exercise (KHE). During the last two weeks of intervention, hindlimb unloading was applied to simulate microgravity. Aerobic exercise groups performed moderate-intensity treadmill running (12 m\/min, 60 min\/day, and 6 days\/week) for 8 weeks. Body weight, blood ketone, and glucose levels were measured weekly. Post-intervention assessments included the respiratory exchange ratio (RER), exhaustive exercise performance tests, and biochemical analyses of blood metabolic parameters. The skeletal muscle fiber-type composition was evaluated via immunofluorescence staining, lipid deposition was assessed using Oil Red O staining, glycogen content was analyzed by Periodic Acid\u2013Schiff (PAS) staining, and gene expression was quantified using quantitative real-time PCR (RT-qPCR). Results: Hindlimb unloading significantly decreased body weight, induced muscle atrophy, and reduced exercise endurance in mice. However, the combination of KD and aerobic exercise significantly attenuated these adverse effects, as evidenced by increased proportions of oxidative muscle fibers (MyHC-I) and decreased proportions of glycolytic fibers (MyHC-IIb). Additionally, this combined intervention upregulated the expression of lipid metabolism-associated genes, including CPT-1b, HADH, PGC-1\u03b1, and FGF21, enhancing lipid metabolism and ketone utilization. These metabolic adaptations corresponded with improved exercise performance, demonstrated by the increased time to exhaustion in the KHE group compared to other hindlimb unloading groups. Conclusions: The combination of a ketogenic diet and aerobic exercise effectively ameliorates simulated microgravity-induced skeletal muscle atrophy and endurance impairment, primarily by promoting a fiber-type transition from MyHC-IIb to MyHC-I and enhancing lipid metabolism gene expression (CPT-1b, HADH, and PGC-1\u03b1). These findings underscore the potential therapeutic value of combined dietary and exercise interventions for mitigating muscle atrophy under simulated microgravity conditions.<\/jats:p>","DOI":"10.3390\/metabo15040270","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T04:42:07Z","timestamp":1744605727000},"page":"270","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Combined Effects of Ketogenic Diet and Aerobic Exercise on Skeletal Muscle Fiber Remodeling and Metabolic Adaptation in Simulated Microgravity Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Jun","family":"Chen","sequence":"first","affiliation":[{"name":"School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China"},{"name":"Sports Nutrition Center, National Institute of Sports Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjiong","family":"Li","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Space Medicine, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhili","family":"Li","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Space Medicine, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zou","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Space Medicine, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bai","family":"Ding","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Space Medicine, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Dai","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Space Medicine, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9388-2916","authenticated-orcid":false,"given":"Qirong","family":"Wang","sequence":"additional","affiliation":[{"name":"Sports Nutrition Center, National Institute of Sports Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1152\/japplphysiol.00489.2023","article-title":"NASA SPRINT Exercise Program Efficacy for Vastus Lateralis and Soleus Skeletal Muscle Health during 70 Days of Simulated Microgravity","volume":"136","author":"Trappe","year":"2024","journal-title":"J. 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