ArticleCell metabolism2021
The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure.
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Article in Cell metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 204 papers.
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204citing papers in PubMed
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204 citing papers in PubMed, 309 citations in OpenAlex.
- Lactylation: Metabolic epigenetic regulation and cell death mechanisms in myocardial ischemia‒reperfusion injury.Genes & diseases · 2027Review
- Heterogeneity in secondary follicle development buffers the lifespan of activated oocytes to optimize female fertility in mice.Nature aging · 2026Article
- Lactylation at the metabolic-epigenetic interface in cardiovascular diseases: context-dependent mechanisms and translational roadmap.Journal of advanced research · 2026Review
- Roles of inflammation and metabolic dysfunction in cardiovascular diseases: molecular mechanisms and therapeutic targets.Molecular biomedicine · 2026Review
- Trilobatin Ameliorates Myocardial Hypertrophy by Enhancing Mitophagy Through Activation of the Sentrin-Specific Protease 1/Sirtuin 3 Axis in Spontaneously Hypertensive Rats.Phytotherapy research : PTR · 2026Article
- Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling.Circulation · 2026Article
- RND3 Enhances Cardiac Glucose Metabolism Through Inhibiting ACAT1-Dependent PDHA1 Acetylation and Protects Against Ischemia-Reperfusion Injury.Circulation · 2026Article
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications.Signal transduction and targeted therapy · 2026Review
- The emerging role of lactate in skeletal homeostasis and disorders: Integrated mechanisms and translational opportunities.Journal of orthopaedic translation · 2026Review
- Mechanistic Studies of Lactate in Heart Failure: From Metabolic Biomarker to Therapeutic Target.Reviews in cardiovascular medicine · 2026Review
- Ginsenoside RK3 attenuates isoproterenol-induced heart failure in mice through AMPK/Sirt1/PGC-1α pathway activation.Journal of ginseng research · 2026Article
- FBP1 Is Associated with Attenuated Mitochondrial Injury in Renal Tubular Epithelial Cells of Diabetic Kidney Disease via Modulation of Lactate Metabolism.International journal of molecular sciences · 2026Article
- Lactate as a Cardiovascular Exerkine: Mechanisms, Signaling Pathways, and Clinical Implications.Biomolecules · 2026Review
- Article
- [Lactate induces gastric mucosal injury by promoting M1 polarization of macrophagesNan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- Lactylation enzymes in cancer: Mechanisms and novel therapeutic approaches (Review).Oncology letters · 2026Review
- Metabolic inflexibility across heart failure phenotypes: mechanisms and type-specific therapeutic implications.Apoptosis : an international journal on programmed cell death · 2026Review
- Lactylation and lactate: insights into muscle cell epigenetic regulators in exercise.Molecular medicine (Cambridge, Mass.) · 2026Review
- Catestatin restores cardiac metabolic flexibility and enhances mitochondrial function.Communications biology · 2026Article
- Lactate and lactylation: mechanisms, function, diseases, and therapeutic targets.Molecular biomedicine · 2026Review
144 more citing papers are in PubMed but not listed here.
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Authors and funding
27 authors at 3 institutions in 1 country.
Ahmad A CluntunDepartment of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
Rachit BadoliaNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
Sandra LettlovaDepartment of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
K Mark ParnellVettore Biosciences, 1700 Owens Street Suite 515, San Francisco, CA 94158, USA.
Thirupura S ShankarNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
Nikolaos A DiakosNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
Kristofor A OlsonDepartment of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
Iosif TalebNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
Sean M TatumDepartment of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, USA.
Jordan A BergDepartment of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
Corey N CunninghamDepartment of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
Tyler Van RyDepartment 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.
Alex J BottDepartment of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
Aspasia Thodou KrokidiNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
Sarah FogartyDepartment 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.
Sophia SkedrosNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
Wojciech I SwiatekDepartment of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
Xuejing YuUniversity of Utah, School of Medicine, Salt Lake City, UT 84132, USA; Division of Cardiothoracic Surgery, Department of Surgery, Salt Lake City, UT 84132, USA.
Bai LuoDrug Discovery Core Facility, University of Utah, Salt Lake City, UT 84112, USA.
Shannon MerxVettore Biosciences, 1700 Owens Street Suite 515, San Francisco, CA 94158, USA.
Sutip NavankasattusasNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
James E CoxDepartment 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.
Gregory S DuckerDepartment of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
William L HollandDepartment of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, USA.
Stephen H McKellarUniversity 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.
Jared RutterDepartment 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.
Stavros G DrakosNora 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.
University of Utah · USHoward Hughes Medical Institute · USIntermountain Healthcare · US
Funding
TRAINING IN CARDIOVASCULAR RESEARCHT32HL007576 · NHLBI · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI Stavros George Drakos, Robin M Shaw · 1985 to 2026
$10.6MProteomics CoreU54DK110858 · NIDDK · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI Anna E Beaudin, JAMES Eric COX · 2016 to 2026
$8.6MInterdisciplinary Training Program in MetabolismT32DK091317 · NIDDK · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI SCOTT A SUMMERS · 2011 to 2026
$4.8MLiver-islet and intra-islet cross talk in alpha cell hyperplasia and beta cell regenerationR01DK112826 · NIDDK · UT SOUTHWESTERN MEDICAL CENTER · PI HOLLAND, WILLIAM L · 2017 to 2025
$3.4MMitochondrial Biochemistry: From Mechanisms to DiseaseR35GM131854 · NIGMS · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI Jared P Rutter · 2019 to 2026
$3.3MUniversity of Utah Interdisciplinary Training Program in Computational Approaches to Diabetes and Metabolism ResearchT32DK110966 · NIDDK · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI Karen Louise Eilbeck, Marcus Guy Pezzolesi · 2016 to 2026
$2.6MMetabolic regulation of intestinal stem cell homeostasisR01CA228346 · NCI · UNIVERSITY OF UTAH · PI RUTTER, JARED P, THUMMEL, CARL S. · 2018 to 2022
$2.3MClinical and Metabolic Signature of Recovered Myocardium in Human Heart FailureR01HL135121 · NHLBI · UNIVERSITY OF UTAH · PI DRAKOS, STAVROS GEORGE · 2017 to 2021
$1.9MSphingolipid-Mediated Dysregulation of Glucose and Energy Homeostasis in the CNSR01DK108833 · NIDDK · UT SOUTHWESTERN MEDICAL CENTER · PI HOLLAND, WILLIAM L · 2016 to 2020
$1.8MCellular Remodeling in Heart Failure and after LVAD UnloadingR01HL132067 · NHLBI · UNIVERSITY OF UTAH · PI DRAKOS, STAVROS GEORGE, SACHSE, FRANK BERND · 2017 to 2020
$1.5MGlycine metabolism in cancer - Research Supplement to Promote Diversity in Health-Related Research; VelascoR00CA215307 · NCI · UNIVERSITY OF UTAH · PI DUCKER, GREGORY S · 2019 to 2021
$814kAgilent 6550 QTOF system for U of UtahS10OD016232 · OD · UNIVERSITY OF UTAH · PI COX, JAMES ERIC · 2013 to 2013
$578kNCI NIH HHS F99 CA253744NCI NIH HHS K00 CA212445NCI NIH HHS R00 CA215307NCI NIH HHS R01 CA228346NHLBI NIH HHS R01 HL132067NHLBI NIH HHS R01 HL135121NHLBI NIH HHS T32 HL007576NIDDK NIH HHS R01 DK108833NIDDK NIH HHS R01 DK112826NIDDK NIH HHS T32 DK091317NIDDK NIH HHS T32 DK110966NIDDK NIH HHS U54 DK110858NIGMS NIH HHS R35 GM131854NIH HHS S10 OD016232NIH HHS S10 OD018210NIH HHS S10 OD021505
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.
Indexed as
AnimalsAnion Transport ProteinsCardiomegalyHeart-Assist DevicesHeart FailureHumansLactic AcidMembrane Potential, MitochondrialMiceMice, Inbred C57BLMice, KnockoutMitochondriaMitochondrial Membrane Transport ProteinsMonocarboxylic Acid TransportersMuscle ProteinsMyocytes, CardiacAnion Transport ProteinsLactic AcidMitochondrial Membrane Transport ProteinsMonocarboxylic Acid TransportersMPC1 pyruvate carrier protein, mouseMPC2 pyruvate carrier protein, mouseMuscle ProteinsPyruvic AcidReactive Oxygen SpeciesRNA, Small InterferingSlc16a4 protein, mousecardiac metabolismheart failurehypertrophylactateLVADMCT4mitochondriaMPCpyruvateVB124
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