Dataset Information

BCKDK Protects against Obesity-Induced Cardiac Remodelling and Dysfunction by Modulating Mitochondrial ROS-Driven JNK/p38 MAPK Signaling

ABSTRACT: Obesity cardiomyopathy (OCM), characterized by diastolic dysfunction, often progresses to obese heart failure with preserved ejection fraction and remains a major clinical challenge. Accumulating evidence indicates that impaired branched-chain amino acid (BCAA) catabolism is present in OCM, and systemic enhancement of BCAA catabolism through global inhibition of branched-chain ketoacid dehydrogenase kinase (BCKDK), a key negative regulator of BCAA oxidation, alleviates cardiac dysfunction. However, whether cardiac-restricted manipulation of BCAA catabolism is sufficient to confer therapeutic benefits remains unknown. Here, we generated an inducible cardiomyocyte-specific BCKDK knockout mouse model to enhance cardiac BCAA catabolism. Unexpectedly, this model fails to improve and instead exacerbates cardiac dysfunction and ventricular remodelling in OCM. Notably, cardiac BCKDK expression is reduced in both OCM mice and obese patients. Cardiomyocyte-specific BCKDK overexpression robustly improves cardiac function and pathological remodelling in OCM, accompanied by further lowering myocardial BCAA levels. Bulk-RNA sequencing and untargeted metabolomics reveal that the cardiomyocyte-specific BCKDK overexpression restore mitochondrial respiratory function and suppress MAPK-driven inflammatory response. Overall, these findings uncover an unanticipated BCAA-independent role of BCKDK in maintaining cardiomyocyte mitochondrial function and restraining inflammatory signalling, positioning BCKDK as a promising therapeutic target for OCM.

ORGANISM(S): Mus musculus

PROVIDER: GSE317489 | GEO | 2026/07/08

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:BACKGROUND: Imbalances in cardiac branched-chain amino acid (BCAA) metabolism and mitochondrial homeostasis are implicated in the onset and development of heart failure. However, the mechanisms triggering the downregulation of cardiac BCAA metabolism in heart failure remain unclear. Here, we identify a novel role of RNA-binding protein GRSF1 (guanine-rich RNA sequence binding factor 1) in post-transcriptionally regulating cell-intrinsic BCAA metabolic pathways, ultimately contributing to the pathogenesis of heart failure.METHODS: We examined GRSF1 expression in the heart tissues of patients with dilated cardiomyopathy and generated mice with cardiomyocyte-specific deletion or overexpression of GRSF1 in vivo to investigate its role in heart failure. The effect of GRSF1 on BCAA homeostasis was assessed through untargeted and targeted metabolomics and mitochondrial function analysis. To elucidate the mechanisms underlying GRSF1-mediated metabolic regulation, we employed mice with cardiomyocyte-specific deletion of BCKDHB, and mice with cardiomyocyte-specific expression of GRSF1 lacking a quasi-RNA recognition motif. RESULTS: GRSF1 expression was significantly decreased in the hearts of patients with heart failure and failing murine hearts. Cardiomyocyte-specific GRSF1 deletion resulted in cardiac dysfunction, spontaneous progression to dilated cardiomyopathy, and heart failure, accompanied by increased cardiac hypertrophy and fibrosis. Conversely, GRSF1 overexpression attenuated cardiac remodeling and heart failure induced by transverse aortic constriction. Mechanistically, GRSF1 maintained BCAA homeostasis and mitochondrial function by directly interacting with the G-tracts in coding region of BCKDHB mRNA through a quasi-RNA recognition motif to promote the stability of BCKDHB mRNA at the post-transcriptional level, thereby increasing its protein expression. Functional recovery mediated by GRSF1 overexpression in cardiomyocytes was partially blocked upon cardiac-specific deletion of BCKDHB.  CONCLUSIONS: Our study identified GRSF1 as a cell-intrinsic metabolic checkpoint that maintains cardiac BCAA homeostasis by regulating BCKDHB mRNA turnover. Targeting GRSF1 may offer therapeutic benefits for heart failure and other cardiometabolic diseases requiring BCAA manipulation.

Dataset Information

BCKDK Protects against Obesity-Induced Cardiac Remodelling and Dysfunction by Modulating Mitochondrial ROS-Driven JNK/p38 MAPK Signaling

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets