Article

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice

Jia-yu Yu1, Nancy Cao2, Christoph D. Rau3, Ro-Po Lee4, Jieping Yang4, Rachel J. Roth Flach5, Lauren Petersen6, Cansheng Zhu7, Yea-Lyn Pak8, Russell A. Miller9, Yunxia Liu1, Yibin Wang1, Zhaoping Li4, Haipeng Sun1, Chen Gao7
1 .Signature Research Program in Cardiovascular and Metabolic Diseases, DukeNUS School of Medicine and National Heart Center of Singapore, Singapore, Singapore
2 School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
3 Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
4 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
5 Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA
6 Health Science Center, University of Utah, Salt Lake City, UT, USA
7 Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA
8 Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
9 La Ronde Pharmaceuticals, Cambridge, MA, USA
Correspondence to: Chen Gao: gaoc3@ucmail.uc.edu,
DOI: 10.1038/s41401-023-01076-9
Received: 3 February 2023
Accepted: 12 March 2023
Advance online: 29 March 2023

Abstract

Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.
Keywords: branched-chain amino acid; metabolism; heart failure

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