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, 3 weeks 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.
Bibliographical noteFunding Information:
This work was supported by: American Heart Association (AHA; grant nos. 16SFRN31810000 to E.D.A. and 15POST22940024 to Y.Z.); Montreal Heart Institute Foundation (CDR); National Institutes of Health (NIH; grant nos. OD019941 to R.M.W., and R01 DK104998 and R00 AR059190 to E.B.T.); T32 (grant no. HL007638 to A.J.R.); American Diabetes Association (grant no. 1-18-PDF-060 (to A.J.R.); and NIH (grant nos. F32 DK101183 to L.R.G., U54DK110858, 1S10OD021505 and 1S10OD018210 to J.E.C., R01HL113057, R01HL132525 and R01HL049244 to E.D.L. and DK091538 to P.A.C.).
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't