The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure

• Published in: Cell metabolism Vol. 33; no. 3; pp. 629 - 648.e10
• Main Authors: Cluntun, Ahmad A., Badolia, Rachit, Lettlova, Sandra, Parnell, K. Mark, Shankar, Thirupura S., Diakos, Nikolaos A., Olson, Kristofor A., Taleb, Iosif, Tatum, Sean M., Berg, Jordan A., Cunningham, Corey N., Van Ry, Tyler, Bott, Alex J., Krokidi, Aspasia Thodou, Fogarty, Sarah, Skedros, Sophia, Swiatek, Wojciech I., Yu, Xuejing, Luo, Bai, Merx, Shannon, Navankasattusas, Sutip, Cox, James E., Ducker, Gregory S., Holland, William L., McKellar, Stephen H., Rutter, Jared, Drakos, Stavros G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.03.2021
• Subjects: Animals; Anion Transport Proteins - antagonists & inhibitors; Anion Transport Proteins - genetics; Anion Transport Proteins - metabolism; cardiac metabolism; Cardiomegaly - chemically induced; Cardiomegaly - complications; Cardiomegaly - pathology; heart failure; Heart Failure - etiology; Heart Failure - pathology; Heart-Assist Devices; Humans; hypertrophy; lactate; Lactic Acid - metabolism; LVAD; MCT4; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Knockout; mitochondria; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Monocarboxylic Acid Transporters - antagonists & inhibitors; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - metabolism; MPC; Muscle Proteins - antagonists & inhibitors; Muscle Proteins - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; pyruvate; Pyruvic Acid - metabolism; Reactive Oxygen Species - metabolism; RNA Interference; RNA, Small Interfering - metabolism; VB124; Ventricular Function, Left - physiology; heart failure; MPC; MCT4; hypertrophy; cardiac metabolism; mitochondria; lactate; pyruvate; VB124; LVAD
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2020.12.003

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. [Display omitted] •Myocardial MPC expression coincides with LVAD-mediated recovery in chronic HF patients•Loss of the MPC in cells or mouse hearts is sufficient to induce hypertrophy and HF•MPC overexpression attenuates drug-induced hypertrophy in a cell-autonomous manner•Inhibition of MCT4 can mitigate hypertrophy in cultured cardiomyocytes and in mice Cluntun et al. identify the pyruvate-lactate axis as a critical node in cardiac homeostasis and health. This axis is maintained by a careful regulation of the disposition of pyruvate, including mitochondrial import and cellular export as lactate. During hypertrophy and heart failure, this balance is disrupted. Regaining this balance by inhibiting MCT4 ameliorated the hypertrophic phenotype.