The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure.
Publication/Presentation Date
3-2-2021
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.
Volume
33
Issue
3
First Page
629
Last Page
648
ISSN
1932-7420
Published In/Presented At
Cluntun, A. A., Badolia, R., Lettlova, S., Parnell, K. M., Shankar, T. S., Diakos, N. A., Olson, K. A., Taleb, I., Tatum, S. M., Berg, J. A., Cunningham, C. N., Van Ry, T., Bott, A. J., Krokidi, A. T., Fogarty, S., Skedros, S., Swiatek, W. I., Yu, X., Luo, B., Merx, S., … Drakos, S. G. (2021). The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell metabolism, 33(3), 629–648.e10. https://doi.org/10.1016/j.cmet.2020.12.003
Disciplines
Medicine and Health Sciences
PubMedID
33333007
Department(s)
Medical Education
Document Type
Article