Journal article
Mitochondrial pyruvate carriers are required for myocardial stress adaptation
Nature metabolism, Vol.2(11), pp.1248-1264
11/01/2020
DOI: 10.1038/s42255-020-00288-1
PMCID: PMC8015649
PMID: 33106689
Abstract
In addition to fatty acids, glucose and lactate are important myocardial substrates under physiologic and stress conditions. They are metabolized to pyruvate, which enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle metabolism. In the present study, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1(-/-)) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate and glycogen, and displayed increased protein O-linked N-acetylglucosamine, which was prevented by increasing availability of non-glucose substrates in vivo by a ketogenic diet (KD) or a high-fat diet, which reversed the structural, metabolic and functional remodelling of non-stressed cMPC1(-/-) hearts. Although concurrent short-term KDs did not rescue cMPC1(-/-) hearts from rapid decompensation and early mortality after pressure overload, 3weeks of a KD before transverse aortic constriction was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function. Metabolic substrate partitioning underlies myocardial homeostatic capacity and adaptation to stress. Zhang et al. show that decreasing mitochondrial pyruvate carrier expression redirects glycolytic intermediates and leads to heart failure, which is prevented or reversed with a high-fat or ketogenic diet.
Details
- Title: Subtitle
- Mitochondrial pyruvate carriers are required for myocardial stress adaptation
- Creators
- Lynn M. Teesch - University of IowaPatrycja Puchalska - University of MinnesotaTrevor R. Funari - Fraternal Order of EaglesRose McGlauflin - Fraternal Order of EaglesKathy Zimmerman - Roy J. and Lucille A. Carver College of MedicineWilliam J. Kutschke - Roy J. and Lucille A. Carver College of MedicineThomas Cassier - Fraternal Order of EaglesShannon Hitchcock - Fraternal Order of EaglesKevin Lin - Fraternal Order of EaglesKevin M. Kato - Fraternal Order of EaglesYuan Zhang - Fraternal Order of EaglesJennifer L. Stueve - Fraternal Order of EaglesLauren Haff - Fraternal Order of EaglesPaul V. Taufalele - Fraternal Order of EaglesRobert M. Weiss - Roy J. and Lucille A. Carver College of MedicineJesse D. Cochran - Fraternal Order of EaglesJames E. Cox - University of UtahIsabelle Robillard-Frayne - Montreal Heart InstituteJonas Maximilian Marx - Friedrich Schiller University JenaJared Rutter - University of UtahJamie Soto - Roy J. and Lucille A. Carver College of MedicineEric B. Taylor - Roy J. and Lucille A. Carver College of MedicineAdam J. Rauckhorst - Fraternal Order of EaglesPeter A. CrawfordE. Douglas Lewandowski - The Ohio State UniversityFariba Tayyari - Roy J. and Lucille A. Carver College of MedicineAlvin D. Pewa - University of IowaChristine Des Rosiers - Univ Montreal, Dept Nutr, Montreal, PQ, CanadaE. Dale Abel - Fraternal Order of EaglesLawrence R. Gray - Fraternal Order of Eagles
- Resource Type
- Journal article
- Publication Details
- Nature metabolism, Vol.2(11), pp.1248-1264
- DOI
- 10.1038/s42255-020-00288-1
- PMID
- 33106689
- PMCID
- PMC8015649
- NLM abbreviation
- Nat Metab
- ISSN
- 2522-5812
- eISSN
- 2522-5812
- Publisher
- Springer Nature
- Number of pages
- 31
- Grant note
- 16SFRN31810000; 15POST22940024 / American Heart Association (AHA); American Heart Association Montreal Heart Institute Foundation OD019941; R01 DK104998; R00 AR059190 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA HL007638 / T32 (grant) 1-18-PDF-060 / American Diabetes Association F32 DK101183; U54DK110858; 1S10OD021505; 1S10OD018210; R01HL113057; R01HL132525; R01HL049244; DK091538 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 11/01/2020
- Academic Unit
- Molecular Physiology and Biophysics; Core Research Facilities; Cardiovascular Medicine; Physical Therapy and Rehabilitation Science; Fraternal Order of Eagles Diabetes Research Center; Medicine Administration; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984297500302771
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