Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia
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 castane...
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MDPI AG
2023-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/9/1330 |
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| author | Yu Zhou Ruohan Lu Fusheng Lin Shu Chen Qi-Qing He Guoyang Wu Caihua Huang Donghai Lin |
| author_facet | Yu Zhou Ruohan Lu Fusheng Lin Shu Chen Qi-Qing He Guoyang Wu Caihua Huang Donghai Lin |
| author_sort | Yu Zhou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T22:59:20Z |
| format | Article |
| id | doaj.art-6709be87e1d84d669358b240fd807837 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T22:59:20Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
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| series | Biomolecules |
| spelling | doaj.art-6709be87e1d84d669358b240fd8078372023-11-19T09:45:29ZengMDPI AGBiomolecules2218-273X2023-08-01139133010.3390/biom13091330Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer CachexiaYu Zhou0Ruohan Lu1Fusheng Lin2Shu Chen3Qi-Qing He4Guoyang Wu5Caihua Huang6Donghai Lin7Key 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, ChinaKey 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, ChinaDepartment of General Surgery, Zhongshan Hospital, Xiamen University, Xiamen 361005, ChinaKey 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, ChinaKey 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, ChinaDepartment of General Surgery, Zhongshan Hospital, Xiamen University, Xiamen 361005, ChinaResearch and Communication Center of Exercise and Health, Xiamen University of Technology, Xiamen 361005, ChinaKey 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, ChinaCachexia (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.https://www.mdpi.com/2218-273X/13/9/1330Ethyl 3-hydroxybutyrate3-hydroxybutyratecancer cachexiaketogenic dietmetabonomics |
| spellingShingle | Yu Zhou Ruohan Lu Fusheng Lin Shu Chen Qi-Qing He Guoyang Wu Caihua Huang Donghai Lin Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia Biomolecules Ethyl 3-hydroxybutyrate 3-hydroxybutyrate cancer cachexia ketogenic diet metabonomics |
| title | Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia |
| title_full | Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia |
| title_fullStr | Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia |
| title_full_unstemmed | Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia |
| title_short | Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia |
| title_sort | exploring the therapeutic potential of ethyl 3 hydroxybutyrate in alleviating skeletal muscle wasting in cancer cachexia |
| topic | Ethyl 3-hydroxybutyrate 3-hydroxybutyrate cancer cachexia ketogenic diet metabonomics |
| url | https://www.mdpi.com/2218-273X/13/9/1330 |
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