Maryam Kay, Anne-Maj Samuelsson, Nike Bharucha, Xueyi Li, Rohin Ramchandani, Rachel E Baum, Diego Ruiz, Aurélie Laguerre, Sherin Lajevardi, Shrikaar Kambhampati, Christian M Metallo, Michael S Kapiloff, Ioannis Karakikes
{"title":"增强心脏丝氨酸生物合成可减轻扩张型心肌病的进展。","authors":"Maryam Kay, Anne-Maj Samuelsson, Nike Bharucha, Xueyi Li, Rohin Ramchandani, Rachel E Baum, Diego Ruiz, Aurélie Laguerre, Sherin Lajevardi, Shrikaar Kambhampati, Christian M Metallo, Michael S Kapiloff, Ioannis Karakikes","doi":"10.1016/j.metabol.2025.156395","DOIUrl":null,"url":null,"abstract":"<p><p>Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. However, disease-modifying therapies remain limited. Metabolic dysfunction has emerged as a key driver of DCM pathogenesis, and impaired serine biosynthesis, catalyzed by the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH), has recently been identified as a potential therapeutic target. Here, we evaluated the therapeutic potential of increasing serine biosynthesis through AAV9-mediated PHGDH gene augmentation in a transgenic TM54 mouse model of DCM with established pathology. Longitudinal echocardiography showed preserved systolic function and prevented ventricular dilatation in TM54 mice treated with AAV9-PHGDH compared to AAV9-GFP controls. Histological analysis revealed reduced myocardial fibrosis and cardiomyocyte hypertrophy in AAV9-PHGDH-treated TM54 hearts, indicating a reversal of pathological remodeling. Metabolic profiling, including targeted metabolomics and in vivo <sup>13</sup>C-glucose tracing analysis, revealed that serine levels increased in hearts treated with AAV9-PHGDH, accompanied by decreases in glucose-derived pyruvate and lactate. At the same time, mitochondrial oxidative metabolism remained intact, indicating a shift of glycolytic carbon towards serine biosynthesis. Collectively, these findings show that enhancing cardiac serine synthesis through PHGDH gene augmentation therapy preserves contractile function and mitigates disease progression in vivo, suggesting a novel metabolic therapeutic strategy for DCM.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156395"},"PeriodicalIF":11.9000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Enhancing cardiac serine biosynthesis mitigates the progression of dilated cardiomyopathy.\",\"authors\":\"Maryam Kay, Anne-Maj Samuelsson, Nike Bharucha, Xueyi Li, Rohin Ramchandani, Rachel E Baum, Diego Ruiz, Aurélie Laguerre, Sherin Lajevardi, Shrikaar Kambhampati, Christian M Metallo, Michael S Kapiloff, Ioannis Karakikes\",\"doi\":\"10.1016/j.metabol.2025.156395\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. However, disease-modifying therapies remain limited. Metabolic dysfunction has emerged as a key driver of DCM pathogenesis, and impaired serine biosynthesis, catalyzed by the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH), has recently been identified as a potential therapeutic target. Here, we evaluated the therapeutic potential of increasing serine biosynthesis through AAV9-mediated PHGDH gene augmentation in a transgenic TM54 mouse model of DCM with established pathology. Longitudinal echocardiography showed preserved systolic function and prevented ventricular dilatation in TM54 mice treated with AAV9-PHGDH compared to AAV9-GFP controls. Histological analysis revealed reduced myocardial fibrosis and cardiomyocyte hypertrophy in AAV9-PHGDH-treated TM54 hearts, indicating a reversal of pathological remodeling. Metabolic profiling, including targeted metabolomics and in vivo <sup>13</sup>C-glucose tracing analysis, revealed that serine levels increased in hearts treated with AAV9-PHGDH, accompanied by decreases in glucose-derived pyruvate and lactate. At the same time, mitochondrial oxidative metabolism remained intact, indicating a shift of glycolytic carbon towards serine biosynthesis. Collectively, these findings show that enhancing cardiac serine synthesis through PHGDH gene augmentation therapy preserves contractile function and mitigates disease progression in vivo, suggesting a novel metabolic therapeutic strategy for DCM.</p>\",\"PeriodicalId\":18694,\"journal\":{\"name\":\"Metabolism: clinical and experimental\",\"volume\":\" \",\"pages\":\"156395\"},\"PeriodicalIF\":11.9000,\"publicationDate\":\"2025-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Metabolism: clinical and experimental\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.metabol.2025.156395\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Metabolism: clinical and experimental","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.metabol.2025.156395","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Enhancing cardiac serine biosynthesis mitigates the progression of dilated cardiomyopathy.
Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. However, disease-modifying therapies remain limited. Metabolic dysfunction has emerged as a key driver of DCM pathogenesis, and impaired serine biosynthesis, catalyzed by the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH), has recently been identified as a potential therapeutic target. Here, we evaluated the therapeutic potential of increasing serine biosynthesis through AAV9-mediated PHGDH gene augmentation in a transgenic TM54 mouse model of DCM with established pathology. Longitudinal echocardiography showed preserved systolic function and prevented ventricular dilatation in TM54 mice treated with AAV9-PHGDH compared to AAV9-GFP controls. Histological analysis revealed reduced myocardial fibrosis and cardiomyocyte hypertrophy in AAV9-PHGDH-treated TM54 hearts, indicating a reversal of pathological remodeling. Metabolic profiling, including targeted metabolomics and in vivo 13C-glucose tracing analysis, revealed that serine levels increased in hearts treated with AAV9-PHGDH, accompanied by decreases in glucose-derived pyruvate and lactate. At the same time, mitochondrial oxidative metabolism remained intact, indicating a shift of glycolytic carbon towards serine biosynthesis. Collectively, these findings show that enhancing cardiac serine synthesis through PHGDH gene augmentation therapy preserves contractile function and mitigates disease progression in vivo, suggesting a novel metabolic therapeutic strategy for DCM.
期刊介绍:
Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism.
Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential.
The journal addresses a range of topics, including:
- Energy Expenditure and Obesity
- Metabolic Syndrome, Prediabetes, and Diabetes
- Nutrition, Exercise, and the Environment
- Genetics and Genomics, Proteomics, and Metabolomics
- Carbohydrate, Lipid, and Protein Metabolism
- Endocrinology and Hypertension
- Mineral and Bone Metabolism
- Cardiovascular Diseases and Malignancies
- Inflammation in metabolism and immunometabolism