Zhou Yu, Lu Ruohan, Lin Fusheng, Chen Shu, He Qi-Qing, Wu Guoyang, Huang Caihua, Lin Donghai
Key Laboratory for Chemical Biology of Fujian Province, MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
Department of General Surgery, Zhongshan Hospital, Xiamen University, Xiamen 361005, China.
Biomolecules. 2023 Aug 30;13(9):1330. doi: 10.3390/biom13091330.
Cachexia (CAC) is a debilitating metabolic syndrome. Although dietary interventions are attractive, long-term adherence to specific diets is difficult to maintain and can lead to systemic side effects. Ethyl 3-hydroxybutyrate (EHB) is a commonly used food additive found in wine and Tribolium castaneum. In this study, we investigated the effects of EHB administration in cachectic mice. After a single intraperitoneal injection of EHB into mice, 3-hydroxybutyrate (3-HB) levels were significantly increased in the serum and gastrocnemius of mice. The administration of EHB alleviated cachexia-related symptoms, ameliorated skeletal muscle atrophy, and improved survival in cachectic mice. In addition, the supplementation of cachectic mice with 3-HB by EHB administration significantly reduced tumor weights, indicating the anti-tumor effects of 3-HB. Remarkably, the addition of 3-HB to the culture medium significantly attenuated the C2C12 myotube atrophy induced by the culture supernatant of CT26 cell lines, highlighting its potential to counteract the destructive effects of tumor-derived elements on muscle tissue. NMR-based metabolomics analysis provided insights into the underlying mechanisms and revealed that the anti-cachexia effects of 3-HB treatment can be attributed to three key mechanisms: the promotion of the TCA cycle and the attenuation of proteolysis, the promotion of protein synthesis and the improvement of metabolic homeostasis, and a reduction in inflammation and an enhancement of the antioxidant capacity. This study provided compelling evidence for the protective effects of 3-HB treatment on the cachectic gastrocnemius and highlighted the efficacy of EHB administration as a ketone supplementation approach to achieve nutritional ketosis without the need for dietary restriction.
恶病质（CAC）是一种使人虚弱的代谢综合征。尽管饮食干预颇具吸引力，但长期坚持特定饮食难以维持，且可能导致全身副作用。3-羟基丁酸乙酯（EHB）是葡萄酒和赤拟谷盗中常见的食品添加剂。在本研究中，我们调查了EHB给药对恶病质小鼠的影响。给小鼠单次腹腔注射EHB后，小鼠血清和腓肠肌中的3-羟基丁酸（3-HB）水平显著升高。EHB给药减轻了恶病质相关症状，改善了骨骼肌萎缩，并提高了恶病质小鼠的存活率。此外，通过EHB给药为恶病质小鼠补充3-HB显著降低了肿瘤重量，表明3-HB具有抗肿瘤作用。值得注意的是，在培养基中添加3-HB显著减轻了CT26细胞系培养上清液诱导的C2C12肌管萎缩，突出了其抵消肿瘤衍生成分对肌肉组织破坏作用的潜力。基于核磁共振的代谢组学分析深入了解了潜在机制，并揭示3-HB治疗的抗恶病质作用可归因于三个关键机制：促进三羧酸循环和减弱蛋白水解、促进蛋白质合成和改善代谢稳态、减轻炎症和增强抗氧化能力。本研究为3-HB治疗对恶病质腓肠肌的保护作用提供了有力证据，并强调了EHB给药作为一种酮补充方法的有效性，可在无需饮食限制的情况下实现营养性酮症。
