| Literature DB >> 33333007 |
Ahmad A Cluntun1, Rachit Badolia2, Sandra Lettlova1, K Mark Parnell3, Thirupura S Shankar2, Nikolaos A Diakos2, Kristofor A Olson1, Iosif Taleb2, Sean M Tatum4, Jordan A Berg1, Corey N Cunningham1, Tyler Van Ry5, Alex J Bott1, Aspasia Thodou Krokidi2, Sarah Fogarty6, Sophia Skedros2, Wojciech I Swiatek1, Xuejing Yu7, Bai Luo8, Shannon Merx3, Sutip Navankasattusas2, James E Cox5, Gregory S Ducker1, William L Holland4, Stephen H McKellar9, Jared Rutter10, Stavros G Drakos11.
Abstract
The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate oxidation and an increased export of lactate. We identify the mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes in this metabolic axis. We observed that cardiac assist device-induced myocardial recovery in chronic HF patients was coincident with increased myocardial expression of the MPC. Moreover, the genetic ablation of the MPC in cultured cardiomyocytes and in adult murine hearts was sufficient to induce hypertrophy and HF. Conversely, MPC overexpression attenuated drug-induced hypertrophy in a cell-autonomous manner. We also introduced a novel, highly potent MCT4 inhibitor that mitigated hypertrophy in cultured cardiomyocytes and in mice. Together, we find that alteration of the pyruvate-lactate axis is a fundamental and early feature of cardiac hypertrophy and failure.Entities:
Keywords: LVAD; MCT4; MPC; VB124; cardiac metabolism; heart failure; hypertrophy; lactate; mitochondria; pyruvate
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Year: 2020 PMID： 33333007 PMCID： PMC7933116 DOI： 10.1016/j.cmet.2020.12.003
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287