The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure

Ahmad A Cluntun; Rachit Badolia; Sandra Lettlova; K Mark Parnell; Thirupura S Shankar; Nikolaos A Diakos; Kristofor A Olson; Iosif Taleb; Sean M Tatum; Jordan A Berg; Corey N Cunningham; Tyler Van Ry; Alex J Bott; Aspasia Thodou Krokidi; Sarah Fogarty; Sophia Skedros; Wojciech I Swiatek; Xuejing Yu; Bai Luo; Shannon Merx; Sutip Navankasattusas; James E Cox; Gregory S Ducker; William L Holland; Stephen H McKellar; Jared Rutter; Stavros G Drakos

doi:10.1016/j.cmet.2020.12.003

The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure

Cell Metab. 2021 Mar 2;33(3):629-648.e10. doi: 10.1016/j.cmet.2020.12.003. Epub 2020 Dec 16.

Authors

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

Affiliations

¹ Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
² Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
³ Vettore Biosciences, 1700 Owens Street Suite 515, San Francisco, CA 94158, USA.
⁴ Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, USA.
⁵ Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA; Metabolomics, Proteomics and Mass Spectrometry Core Facility, University of Utah, Salt Lake City, UT 84112, USA.
⁶ Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
⁷ University of Utah, School of Medicine, Salt Lake City, UT 84132, USA; Division of Cardiothoracic Surgery, Department of Surgery, Salt Lake City, UT 84132, USA.
⁸ Drug Discovery Core Facility, University of Utah, Salt Lake City, UT 84112, USA.
⁹ University of Utah, School of Medicine, Salt Lake City, UT 84132, USA; Division of Cardiothoracic Surgery, Department of Surgery, Salt Lake City, UT 84132, USA; U.T.A.H. (Utah Transplant Affiliated Hospitals) Cardiac Transplant Program: University of Utah Healthcare and School of Medicine, Intermountain Medical Center, Salt Lake VA (Veterans Affairs) Health Care System, Salt Lake City, UT, USA.
¹⁰ Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. Electronic address: rutter@biochem.utah.edu.
¹¹ Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA; U.T.A.H. (Utah Transplant Affiliated Hospitals) Cardiac Transplant Program: University of Utah Healthcare and School of Medicine, Intermountain Medical Center, Salt Lake VA (Veterans Affairs) Health Care System, Salt Lake City, UT, USA. Electronic address: stavros.drakos@hsc.utah.edu.

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.

Keywords: LVAD; MCT4; MPC; VB124; cardiac metabolism; heart failure; hypertrophy; lactate; mitochondria; pyruvate.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anion Transport Proteins / antagonists & inhibitors
Anion Transport Proteins / genetics
Anion Transport Proteins / metabolism*
Cardiomegaly / chemically induced
Cardiomegaly / complications
Cardiomegaly / pathology*
Heart Failure / etiology
Heart Failure / pathology*
Heart-Assist Devices
Humans
Lactic Acid / metabolism
Membrane Potential, Mitochondrial
Mice
Mice, Inbred C57BL
Mice, Knockout
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*
Muscle Proteins / antagonists & inhibitors
Muscle Proteins / metabolism*
Myocytes, Cardiac / cytology
Myocytes, Cardiac / metabolism
Pyruvic Acid / metabolism
RNA Interference
RNA, Small Interfering / metabolism
Reactive Oxygen Species / metabolism
Ventricular Function, Left / physiology

Substances

Anion Transport Proteins
MPC1 pyruvate carrier protein, mouse
MPC2 pyruvate carrier protein, mouse
Mitochondrial Membrane Transport Proteins
Monocarboxylic Acid Transporters
Muscle Proteins
RNA, Small Interfering
Reactive Oxygen Species
Slc16a4 protein, mouse
Lactic Acid
Pyruvic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding