Chen Jun, Li Wenjiong, Yu Liang, Zhang Bowei, Li Zhili, Zou Peng, Ding Bai, Dai Xiaoqian, Wang Qirong
School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China.
Sports Nutrition Center, National Institute of Sports Medicine, Beijing 100029, China.
Metabolites. 2025 Apr 13;15(4):270. doi: 10.3390/metabo15040270.
Prolonged microgravity environments impair skeletal muscle homeostasis by triggering fiber-type transitions and metabolic dysregulation. 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. 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-Schiff (PAS) staining, and gene expression was quantified using quantitative real-time PCR (RT-qPCR). 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-1α, 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. 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-1α). These findings underscore the potential therapeutic value of combined dietary and exercise interventions for mitigating muscle atrophy under simulated microgravity conditions.
长期的微重力环境通过引发纤维类型转变和代谢失调来损害骨骼肌稳态。尽管运动和营养干预可能减轻废用性萎缩，但它们在微重力条件下的协同作用仍未得到充分表征。本研究调查了为期8周的生酮饮食联合有氧运动对后肢卸载小鼠肌肉纤维重塑和代谢适应的影响。将7周龄雄性C57BL/6J小鼠随机分为六组：正常饮食对照组（NC）、后肢卸载的正常饮食组（NH）、后肢卸载并运动的正常饮食组（NHE）、生酮饮食对照组（KC）、后肢卸载的生酮饮食组（KH）以及后肢卸载并运动的生酮饮食组（KHE）。在干预的最后两周，施加后肢卸载以模拟微重力。有氧运动组进行中等强度跑步机跑步（12米/分钟，每天60分钟，每周6天），持续8周。每周测量体重、血酮和血糖水平。干预后评估包括呼吸交换率（RER）、力竭运动性能测试以及血液代谢参数的生化分析。通过免疫荧光染色评估骨骼肌纤维类型组成，使用油红O染色评估脂质沉积，通过过碘酸希夫（PAS）染色分析糖原含量，并使用定量实时PCR（RT-qPCR）定量基因表达。后肢卸载显著降低了小鼠体重，诱导了肌肉萎缩，并降低了运动耐力。然而，生酮饮食与有氧运动的组合显著减轻了这些不利影响，表现为氧化型肌纤维（MyHC-I）比例增加和糖酵解型纤维（MyHC-IIb）比例降低。此外，这种联合干预上调了脂质代谢相关基因的表达，包括CPT-1b、HADH、PGC-1α和FGF21，增强了脂质代谢和酮体利用。这些代谢适应与运动性能的改善相对应，KHE组与其他后肢卸载组相比，力竭时间增加证明了这一点。生酮饮食与有氧运动的组合有效地改善了模拟微重力诱导的骨骼肌萎缩和耐力损害，主要是通过促进从MyHC-IIb到MyHC-I的纤维类型转变以及增强脂质代谢基因表达（CPT-1b、HADH和PGC-1α）。这些发现强调了联合饮食和运动干预在减轻模拟微重力条件下肌肉萎缩方面的潜在治疗价值。
