Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Nutritional modulation of heart failure in mitochondrial pyruvate carrier–deficient mice

Nature Metabolism volume 2, pages 1232–1247 (2020)Cite this article

Subjects

Abstract

The myocardium is metabolically flexible; however, impaired flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) complex, composed of MPC1 and MPC2, is required for pyruvate import into the mitochondria. Here we show that MPC1 and MPC2 expression is downregulated in failing human and mouse hearts. Mice with cardiac-specific deletion of Mpc2 (CS-MPC2−/−) exhibited normal cardiac size and function at 6 weeks old, but progressively developed cardiac dilation and contractile dysfunction, which was completely reversed by a high-fat, low-carbohydrate ketogenic diet. Diets with higher fat content, but enough carbohydrate to limit ketosis, also improved heart failure, while direct ketone body provisioning provided only minor improvements in cardiac remodelling in CS-MPC2−/− mice. An acute fast also improved cardiac remodelling. Together, our results reveal a critical role for mitochondrial pyruvate use in cardiac function, and highlight the potential of dietary interventions to enhance cardiac fat metabolism to prevent or reverse cardiac dysfunction and remodelling in the setting of MPC deficiency.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MPCs are downregulated in human heart failure, and deletion of cardiac MPC2 results in TCA cycle dysfunction.
Fig. 2: CS-MPC2−/− mice develop dilated cardiomyopathy.
Fig. 3: KD can prevent heart failure in CS-MPC2−/− mice.
Fig. 4: KD downregulates cardiac ketone body catabolism.
Fig. 5: KD enhances cardiac fatty acid metabolism.
Fig. 6: HF diets also prevent cardiac remodelling and dysfunction in CS-MPC2−/− mice.
Fig. 7: Improved cardiac remodelling during fasting is associated with enhanced fat oxidation.
Fig. 8: KD can reverse heart failure in CS-Mpc2−/− mice.

Similar content being viewed by others

Data availability

All data from these studies are contained within this manuscript, the figures, and extended/supplemental figures and tables. Data are also available from the corresponding author upon reasonable request. Source data are provided with this paper.

References

  1. Bing, R. J., Siegel, A., Ungar, I. & Gilbert, M. Metabolism of the human heart. II. Studies on fat, ketone and amino acid metabolism. Am. J. Med. 16, 504–515 (1954).

    CAS  PubMed  Google Scholar 

  2. Wisneski, J. A., Gertz, E. W., Neese, R. A. & Mayr, M. Myocardial metabolism of free fatty acids. Studies with 14C-labeled substrates in humans. J. Clin. Invest. 79, 359–366 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lopaschuk, G. D. & Spafford, M. A. Energy substrate utilization by isolated working hearts from newborn rabbits. Am. J. Physiol. 258, H1274–H1280 (1990).

    CAS  PubMed  Google Scholar 

  4. Glatz, J. F. & Veerkamp, J. H. Postnatal development of palmitate oxidation and mitochondrial enzyme activities in rat cardiac and skeletal muscle. Biochim. Biophys. Acta 711, 327–335 (1982).

    CAS  PubMed  Google Scholar 

  5. Lopaschuk, G. D., Spafford, M. A. & Marsh, D. R. Glycolysis is predominant source of myocardial ATP production immediately after birth. Am. J. Physiol. 261, H1698–H1705 (1991).

    CAS  PubMed  Google Scholar 

  6. Kaijser, L. & Berglund, B. Myocardial lactate extraction and release at rest and during heavy exercise in healthy men. Acta Physiol. Scand. 144, 39–45 (1992).

    CAS  PubMed  Google Scholar 

  7. Vanoverschelde, J. L. et al. Competition between palmitate and ketone bodies as fuels for the heart: study with positron emission tomography. Am. J. Physiol. 264, H701–H707 (1993).

    CAS  PubMed  Google Scholar 

  8. Jeffrey, F. M., Diczku, V., Sherry, A. D. & Malloy, C. R. Substrate selection in the isolated working rat heart: effects of reperfusion, afterload, and concentration. Basic Res. Cardiol. 90, 388–396 (1995).

    CAS  PubMed  Google Scholar 

  9. Stanley, W. C., Meadows, S. R., Kivilo, K. M., Roth, B. A. & Lopaschuk, G. D. beta-Hydroxybutyrate inhibits myocardial fatty acid oxidation in vivo independent of changes in malonyl-CoA content. Am. J. Physiol. Heart Circ. Physiol. 285, H1626–H1631 (2003).

    CAS  PubMed  Google Scholar 

  10. Garnier, A. et al. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J. Physiol. 551, 491–501 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Heinke, M. Y. et al. Changes in myocardial protein expression in pacing-induced canine heart failure. Electrophoresis 20, 2086–2093 (1999).

    CAS  PubMed  Google Scholar 

  12. Ide, T. et al. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ. Res. 88, 529–535 (2001).

    CAS  PubMed  Google Scholar 

  13. Marin-Garcia, J., Goldenthal, M. J. & Moe, G. W. Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure. Cardiovasc. Res. 52, 103–110 (2001).

    CAS  PubMed  Google Scholar 

  14. Sack, M. N. et al. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 94, 2837–2842 (1996).

    CAS  PubMed  Google Scholar 

  15. Warren, J. S., Oka, S. I., Zablocki, D. & Sadoshima, J. Metabolic reprogramming via PPARalpha signaling in cardiac hypertrophy and failure: from metabolomics to epigenetics. Am. J. Physiol. Heart Circ. Physiol. 313, H584–H596 (2017).

    PubMed  PubMed Central  Google Scholar 

  16. Barger, P. M., Brandt, J. M., Leone, T. C., Weinheimer, C. J. & Kelly, D. P. Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J. Clin. Invest. 105, 1723–1730 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Taegtmeyer, H. & Overturf, M. L. Effects of moderate hypertension on cardiac function and metabolism in the rabbit. Hypertension 11, 416–426 (1988).

    CAS  PubMed  Google Scholar 

  18. Zhabyeyev, P. et al. Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload. Cardiovasc. Res. 97, 676–685 (2013).

    CAS  PubMed  Google Scholar 

  19. Herzig, S. et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science 337, 93–96 (2012).

    CAS  PubMed  Google Scholar 

  20. Bricker, D. K. et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337, 96–100 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chambers, K. T. et al. Chronic inhibition of pyruvate dehydrogenase in heart triggers an adaptive metabolic response. J. Biol. Chem. 286, 11155–11162 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhao, G. et al. Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 294, H936–H943 (2008).

    CAS  PubMed  Google Scholar 

  23. Gopal, K. et al. Cardiac-specific deletion of pyruvate dehydrogenase impairs glucose oxidation rates and induces diastolic dysfunction. Front Cardiovasc. Med. 5, 17 (2018).

    PubMed  PubMed Central  Google Scholar 

  24. Sun, W. et al. Cardiac-specific deletion of the Pdha1 gene sensitizes heart to toxicological actions of ischemic stress. Toxicol. Sci. 151, 193–203 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Sheeran, F. L., Angerosa, J., Liaw, N. Y., Cheung, M. M. & Pepe, S. Adaptations in protein expression and regulated activity of pyruvate dehydrogenase multienzyme complex in human systolic heart failure. Oxid. Med. Cell Longev. 2019, 4532592 (2019).

    PubMed  PubMed Central  Google Scholar 

  26. McCommis, K. S. et al. Loss of mitochondrial pyruvate carrier 2 in the liver leads to defects in gluconeogenesis and compensation via pyruvate-alanine cycling. Cell Metab. 22, 682–694 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. McCommis, K. S. et al. An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion. Mol. Metab. 5, 602–614 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. McCommis, K. S. et al. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology 65, 1543–1556 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen, J., Kubalak, S. W. & Chien, K. R. Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. Development 125, 1943–1949 (1998).

    CAS  PubMed  Google Scholar 

  30. Halestrap, A. P. & Denton, R. M. The specificity and metabolic implications of the inhibition of pyruvate transport in isolated mitochondria and intact tissue preparations by alpha-Cyano-4-hydroxycinnamate and related compounds. Biochem. J. 148, 97–106 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Aubert, G. et al. The failing heart relies on ketone bodies as a fuel. Circulation 133, 698–705 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bedi, K. C. Jr. et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation 133, 706–716 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Horton, J. L. et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight 4, e124079 (2019).

    PubMed Central  Google Scholar 

  34. Sciarretta, S., Forte, M., Frati, G. & Sadoshima, J. New insights into the role of mTOR signaling in the cardiovascular system. Circ. Res. 122, 489–505 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wentz, A. E. et al. Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment. J. Biol. Chem. 285, 24447–24456 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Ford, D. A., Han, X., Horner, C. C. & Gross, R. W. Accumulation of unsaturated acylcarnitine molecular species during acute myocardial ischemia: metabolic compartmentalization of products of fatty acyl chain elongation in the acylcarnitine pool. Biochemistry 35, 7903–7909 (1996).

    CAS  PubMed  Google Scholar 

  37. Martin, M. A. et al. Myocardial carnitine and carnitine palmitoyltransferase deficiencies in patients with severe heart failure. Biochim. Biophys. Acta 1502, 330–336 (2000).

    CAS  PubMed  Google Scholar 

  38. Stanley, W. C., Recchia, F. A. & Lopaschuk, G. D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85, 1093–1129 (2005).

    CAS  PubMed  Google Scholar 

  39. Shearman, M. S. & Halestrap, A. P. The concentration of the mitochondrial pyruvate carrier in rat liver and heart mitochondria determined with alpha-cyano-beta-(1-phenylindol-3-yl)acrylate. Biochem. J. 223, 673–676 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Hildyard, J. C., Ammala, C., Dukes, I. D., Thomson, S. A. & Halestrap, A. P. Identification and characterisation of a new class of highly specific and potent inhibitors of the mitochondrial pyruvate carrier. Biochim. Biophys. Acta 1707, 221–230 (2005).

    CAS  PubMed  Google Scholar 

  41. Bunger, R. & Mallet, R. T. Mitochondrial pyruvate transport in working guinea-pig heart. Work-related vs. carrier-mediated control of pyruvate oxidation. Biochim. Biophys. Acta 1151, 223–236 (1993).

    CAS  PubMed  Google Scholar 

  42. Fernandez-Caggiano, M. et al. Analysis of mitochondrial proteins in the surviving myocardium after ischemia identifies mitochondrial pyruvate carrier expression as possible mediator of tissue viability. Mol. Cell Proteom. 15, 246–255 (2016).

    CAS  Google Scholar 

  43. Fernandez-Caggiano, M. et al. Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy. Nat. Metabol. https://doi.org/10.1038/s42255-020-00276-5 (2020).

  44. Zhang, Y. et al. Mitochondrial pyruvate carriers are required for myocardial stress adaptation. Nat. Metabol. https://doi.org/10.1038/s42255-020-00288-1 (2020).

  45. Malloy, C. R., Sherry, A. D. & Jeffrey, F. M. Evaluation of carbon flux and substrate selection through alternate pathways involving the citric acid cycle of the heart by 13C NMR spectroscopy. J. Biol. Chem. 263, 6964–6971 (1988).

    CAS  PubMed  Google Scholar 

  46. Sundqvist, K. E., Hiltunen, J. K. & Hassinen, I. E. Pyruvate carboxylation in the rat heart. Role of biotin-dependent enzymes. Biochem J. 257, 913–916 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Karlstaedt, A. et al. Oncometabolite d-2-hydroxyglutarate impairs alpha-ketoglutarate dehydrogenase and contractile function in rodent heart. Proc. Natl Acad. Sci. USA 113, 10436–10441 (2016).

    CAS  PubMed  Google Scholar 

  48. Akbay, E. A. et al. d-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev. 28, 479–490 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Karlstaedt, A., Khanna, R., Thangam, M. & Taegtmeyer, H. Glucose 6-phosphate accumulates via phosphoglucose isomerase inhibition in heart muscle. Circ. Res. 126, 60–74 (2020).

    CAS  PubMed  Google Scholar 

  50. Ritterhoff, J. et al. Metabolic remodeling promotes cardiac hypertrophy by directing glucose to aspartate biosynthesis. Circ. Res. 126, 182–196 (2020).

    CAS  PubMed  Google Scholar 

  51. Sung, M. M. et al. AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism. Cardiovasc. Res. 107, 235–245 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Xing, Y. et al. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. J. Biol. Chem. 278, 28372–28377 (2003).

    CAS  PubMed  Google Scholar 

  53. Zarrinpashneh, E. et al. AMPKalpha2 counteracts the development of cardiac hypertrophy induced by isoproterenol. Biochem. Biophys. Res. Commun. 376, 677–681 (2008).

    CAS  PubMed  Google Scholar 

  54. Kim, M. et al. Mutation in the gamma2-subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage. Circ. Res. 114, 966–975 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Nielsen, R. et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation 139, 2129–2141 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Uchihashi, M. et al. Cardiac-specific Bdh1 overexpression ameliorates oxidative stress and cardiac remodeling in pressure overload-induced heart failure. Circ. Heart. Fail. 10, e004417 (2017).

  57. Schugar, R. C. et al. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Mol. Metab. 3, 754–769 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Pereyra, A. S. et al. Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy. J. Biol. Chem. 292, 18443–18456 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Halestrap, A. P. Pyruvate and ketone-body transport across the mitochondrial membrane. Exchange properties, pH-dependence and mechanism of the carrier. Biochem. J. 172, 377–387 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Gray, L. R. et al. Hepatic mitochondrial pyruvate carrier 1 is required for efficient regulation of gluconeogenesis and whole-body glucose homeostasis. Cell Metab. 22, 669–681 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. National Institutes of Health. Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011).

  62. Chen, J. et al. Selective requirement of myosin light chain 2v in embryonic heart function. J. Biol. Chem. 273, 1252–1256 (1998).

    CAS  PubMed  Google Scholar 

  63. Vigueira, P. A. et al. Mitochondrial pyruvate carrier 2 hypomorphism in mice leads to defects in glucose-stimulated insulin secretion. Cell Rep. 7, 2042–2053 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Bowman, C. E., Zhao, L., Hartung, T. & Wolfgang, M. J. Requirement for the mitochondrial pyruvate carrier in mammalian development revealed by a hypomorphic allelic series. Mol. Cell. Biol. 36, 2089–2104 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Exil, V. J. et al. Very-long-chain acyl-coenzyme a dehydrogenase deficiency in mice. Circ. Res. 93, 448–455 (2003).

    CAS  PubMed  Google Scholar 

  66. Hainline, B. E., Kahlenbeck, D. J., Grant, J. & Strauss, A. W. Tissue specific and developmental expression of rat long-and medium-chain acyl-CoA dehydrogenases. Biochim. Biophys. Acta 1216, 460–468 (1993).

    CAS  PubMed  Google Scholar 

  67. Kelly, D. P. et al. Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue. Proc. Natl Acad. Sci. USA 84, 4068–4072 (1987).

    CAS  PubMed  Google Scholar 

  68. An, J. et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat. Med. 10, 268–274 (2004).

    CAS  PubMed  Google Scholar 

  69. Ferrara, C. T. et al. Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling. PLoS Genet. 4, e1000034 (2008).

    PubMed  PubMed Central  Google Scholar 

  70. Millington, D. S. & Stevens, R. D. Acylcarnitines: analysis in plasma and whole blood using tandem mass spectrometry. Methods Mol. Biol. 708, 55–72 (2011).

    CAS  PubMed  Google Scholar 

  71. Chace, D. H. et al. Rapid diagnosis of phenylketonuria by quantitative analysis for phenylalanine and tyrosine in neonatal blood spots by tandem mass spectrometry. Clin. Chem. 39, 66–71 (1993).

    CAS  PubMed  Google Scholar 

  72. Jensen, M. V. et al. Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion. J. Biol. Chem. 281, 22342–22351 (2006).

    CAS  PubMed  Google Scholar 

  73. Khomtchouk, B. B., Hennessy, J. R. & Wahlestedt, C. shinyheatmap: Ultra fast low memory heatmap web interface for big data genomics. PLoS One 12, e0176334 (2017).

    PubMed  PubMed Central  Google Scholar 

  74. Gao, L. et al. Simultaneous quantification of malonyl-CoA and several other short-chain acyl-CoAs in animal tissues by ion-pairing reversed-phase HPLC/MS. J. Chromatogr. B. Anal. Technol. Biomed. Life Sci. 853, 303–313 (2007).

    CAS  Google Scholar 

  75. Weinheimer, C. J., Lai, L., Kelly, D. P. & Kovacs, A. Novel mouse model of left ventricular pressure overload and infarction causing predictable ventricular remodelling and progression to heart failure. Clin. Exp. Pharm. Physiol. 42, 33–40 (2015).

    CAS  Google Scholar 

  76. Teichholz, L. E., Kreulen, T., Herman, M. V. & Gorlin, R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence of absence of asynergy. Am. J. Cardiol. 37, 7–11 (1976).

    CAS  PubMed  Google Scholar 

  77. Kronik, G., Slany, J. & Mosslacher, H. Comparative value of eight M-mode echocardiographic formulas for determining left ventricular stroke volume. A correlative study with thermodilution and left ventricular single-plane cineangiography. Circulation 60, 1308–1316 (1979).

    CAS  PubMed  Google Scholar 

  78. Weinheimer, C. J. et al. Load-dependent changes in left ventricular structure and function in a pathophysiologically relevant murine model of reversible heart failure. Circ. Heart Fail. 11, e004351 (2018).

    PubMed  PubMed Central  Google Scholar 

  79. Suzuki, Y. et al. Insulin control of glycogen metabolism in knockout mice lacking the muscle-specific protein phosphatase PP1G/RGL. Mol. Cell. Biol. 21, 2683–2694 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We sadly note that, Richard (Bud) L. Veech passed away at the age of 84 during the preparation of this manuscript. We thank him for providing the ketone ester diet and his enthusiasm toward this project. This work was supported by core resources of the Nutrition Obesity Research Center (NORC) (P30 DK56341), Diabetes Research Center (DRC) (P30 DK020579), and Institute for Clinical and Translational Sciences (ICTS) (UL1 TR002345) at the Washington University School of Medicine. NIH grant nos. K99/R00 HL136658 (to K.S.M.), R01 HL133178 (to R.W.G.) and R01 HL119225 and R01 DK104735 (to B.N.F.) supported these studies.

Author information

Authors and Affiliations

  1. Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Kyle S. McCommis, Attila Kovacs, Carla J. Weinheimer, Trevor M. Shew, Richard W. Gross & Brian N. Finck

  2. Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA

    Kyle S. McCommis, Dakota R. Kamm & Kelly D. Pyles

  3. Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA

    Timothy R. Koves, Olga R. Ilkayeva & Deborah M. Muoio

  4. Laboratory of Metabolic Control, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA

    M. Todd King & Richard L. Veech

  5. Departments of Pediatrics and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA

    Brian J. DeBosch

  6. Department of Chemistry, Washington University, St. Louis, MO, USA

    Richard W. Gross

Authors
  1. Kyle S. McCommis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Attila Kovacs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carla J. Weinheimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Trevor M. Shew
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Timothy R. Koves
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Olga R. Ilkayeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dakota R. Kamm
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kelly D. Pyles
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Todd King
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Richard L. Veech
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Brian J. DeBosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Deborah M. Muoio
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Richard W. Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Brian N. Finck
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.S.M. and B.N.F. conceived the study. K.S.M., A.K., C.J.W., T.M.S., T.R.K., O.R.I., D.M.M. and B.N.F. designed the study. Acquisition and analysis were conducted by K.S.M., A.K., C.J.W., T.R.K., O.R.I., D.R.K. and K.D.P. The resources were obtained by M.T.K., R.L.V., B.J.D. and R.W.G. Writing and editing of the manuscript were done by K.S.M., A.K., C.J.W., T.M.S., T.R.K., O.R.I., D.M.M., D.R.K., K.D.P., M.T.K., B.J.D., R.W.G. and B.N.F.

Corresponding author

Correspondence to Kyle S. McCommis.

Ethics declarations

Competing interests

K.S.M. previously received research support from Cirius Therapeutics, and B.N.F. is a stockholder and scientific advisory board member of Cirius Therapeutics. R.L.V. held patents on the synthesis and uses of ketone esters, and M.T.K. is a coinventor in the synthesis of ketone esters. All other authors have declared that no competing interests exist.

Additional information

Peer review information Primary Handling Editor: George Caputa.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Human heart failure gene expression and characterization of 6-week old CS-MPC2−/− mice.

Gene expression from human non-failing, failing, and failing hearts after left ventricular assist device (LVAD) placement (n = 14, 9, and 6 for Non-failing, Failing, and Post-LVAD, respectively). c-d, MPC1 and MPC2 protein expression quantification from non-failing and failing human hearts normalized to either VDAC, complex I and II, complexes III and IV, or Tubulin (n = 5). e, Gene expression for Mpc1 and Mpc2 from wildtype C57BL6/J mouse hearts after sham or transverse aortic constriction plus myocardial infarction (TAC + MI) surgery (n = 9 sham, 12 TAC-MI). f, Mouse heart gene expression for Mpc1 and Mpc2 (n = 7, 5, 7 for fl/fl, +/−, −/− respectively). g, Blood lactate measured after a 4 h fast prior to sacrifice in 6-week old mice (n = 6). h-i, Heart weight and lung weight of 6-week old mice (n = 6). j, Mouse heart gene expression of heart failure, and hypertrophy genes from 6-week old mice (n = 7, 5, 7 for fl/fl, +/−, −/− respectively). Data are presented as mean ± s.e.m. within dot plot. Each data point represents one individual mouse or sample. Two-tailed unpaired Student’s t test.

Extended Data Fig. 2 Heart failure develops in CS-MPC2−/− mice, but not CS-MPC2 +/− or mice treated with the MPC inhibitor MSDC-0602K.

a-h, Serial echocardiography data of chow-fed mice at 6, 10, and 16 weeks of age. Left ventricular internal diameter at end diastole (LVIDd) and end systole (LVIDs), end systolic volume (ESV), fractional shortening (FS), relative wall thickness (RWT), stroke volume (SV), and cardiac output (CO) (n = 7, 10, and 9 for fl/fl, +/−, and −/−, respectively). i, Heart weights from WT mice fed low fat (LF) diet or a high trans-fat, fructose, cholesterol (HTF-C) diet +/− 330 ppm MSDC-0602, an insulin-sensitizing MPC inhibitor (n = 7, 9, and 9 for LF, HTF-C, and HTF-C + MSDC-0602K, respectively). j, Heart gene expression of hypertrophy gene markers from WT mice fed LF, HTF-C, or HTF-C + MSDC-0602 diets (n = 6 for all groups). k-l, Heart gene expression for fatty acid transport and oxidation genes and PPARα target genes from chow-fed 16-week old mice after a 4 h fast (n = 7, 5, and 7 for fl/fl, +/−, and −/−, respectively). Data are presented as mean ± s.e.m., or mean ± s.e.m. within dot plot. Each data point represents one individual mouse or sample. Two-tailed unpaired Student’s t test.

Extended Data Fig. 3 Ketogenic diet prevents heart failure in CS-MPC2−/− mice.

a, Body weights of mice fed low fat (LF) or ketogenic diet (KD) from 6-17 weeks of age (initial n = 19, 15, 21, and 14 for fl/fl LF, CS-Mpc2−/− LF, fl/fl KD, and CS-Mpc2−/− KD, respectively)(fl/fl LF vs KD p < 0.0001; CS-Mpc2−/− LF vs KD p < 0.0001). b-c, Blood glucose and plasma insulin measured after a 4 h fast (n = 19, 11, 20, and 14, respectively for glucose and 8, 5, 9, and 7, respectively for insulin). d-n, Echocardiography data at 10 and 16 weeks of age. Left ventricular internal diameter at end diastole (LVIDd) and end systole (LVIDs), fractional shortening (FS), relative wall thickness (RWT), end diastolic volume (EDV), end systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and cardiac output (CO) (n = 9, 7, 12, and 9 for fl/fl LF, CS-Mpc2−/− LF, fl/fl KD, and CS-Mpc2−/− KD, respectively). o-q, % Fat mass, % lean mass, and % free water body composition measured by echoMRI (n = 19, 12, 20, and 14, respectively). r-s, Gonadal and inguinal white adipose tissue (WAT) weights normalized to body weight (n = 19, 12, 20, and 14, respectively). Data are presented as mean ± s.e.m. or mean ± s.e.m. within dot plot. Each data point in dot plot represents one individual mouse sample. Two-way ANOVA with Tukey’s multiple comparisons test. For d-n, black p values indicate LF-fed fl/fl vs. CS-Mpc2−/−, red p values indicate LF vs. KD for CS-Mpc2−/− for each echocardiography date.

Extended Data Fig. 4 Ketone body injection modestly reduces cardiac remodeling in CS-MPC2−/− mice.

a, Timeline for β-hydroxybutyrate (βHB) injection experiment in which CS-MPC2−/− mice were injected i.p. with saline vehicle or 10 mmol/kg βHB daily from 12 to 14 weeks of age. b-h, Echocardiography measurements before and after 2 weeks of daily i.p. injection of saline vehicle (Veh) or 10 mmol/kg β-hydroxybutyrate. Left ventricular (LV) mass index, end-diastolic volume (EDV), end-systolic volume (ESV), heart rate (HR), relative wall thickness (RWT), ejection fraction (EF), and cardiac output (CO) (n = 4 Veh, 5 βHB). i, Plasma total ketone body concentrations (n = 4 Veh, 5 βHB). j, Heart weight normalized to tibia length (n = 4 Veh, 5 βHB). k, Gene expression markers of hypertrophy, heart failure, and fibrosis from hearts after 2 weeks of daily vehicle or βHB treatment (n = 4 Veh, 5 βHB). Data presented either as PRE-POST, or mean ± s.e.m. shown within dot plot. Each symbol represents an individual sample. Two-tailed unpaired Student’s t test.

Extended Data Fig. 5 Ketone ester diet does not improve cardiac remodeling or function in CS-MPC2−/− mice.

a, Plasma ketone bodies measured from mice fed either control or ketone ester (KE)-supplemented diet (n = 10, 7, 4, and 8, respectively). b-e, Echocardiography measurements after 6 weeks of KE diet feeding. Left ventricular (LV) mass index, end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) (n = 10, 7, 4, and 8, respectively). f, Heart weight normalized to tibia length (n = 10, 7, 4, and 8, respectively). g-i, Cardiac gene expression markers of hypertrophy and heart failure (Nppa, Nppb, Acta1) (n = 10, 7, 4, and 8, respectively). Data presented as mean ± s.e.m. shown within dot plot. Each symbol represents an individual sample. Two-way ANOVA with Tukey’s multiple comparisons test.

Extended Data Fig. 6 High-fat diets also greatly improve cardiac remodeling and function of CS-MPC2−/− mice.

a-I, Echocardiography measurements taken at 16 weeks of age after 10 weeks of low fat (LF), medium chain triglyceride (MCT), or high-fat (HF) feeding. Left ventricular internal diameter at end diastole (LVIDd) and end systole (LVIDs), fractional shortening (FS), relative wall thickness (RWT), end diastolic volume (EDV), end systolic volume (ESV), stroke volume (SV), and cardiac output (CO) (n = 5, 4, 4, 8, 4, and 5, respectively). j-l, Cardiac gene expression for Ppara and it’s targets Acot1 and Hmgcs2 (n = 11, 6, 10, 8, 4, and 5, respectively). Data are presented as mean ± s.e.m. within dot plot. Each data point represents an individual mouse. Two-way ANOVA with Tukey’s multiple comparisons test.

Extended Data Fig. 7 A 24 hour fast improves cardiac remodeling by enhancing fat oxidation.

a, Blood lactate of fed or fasted mice just prior to euthanasia (n = 22, 15, 16, and 14, respectively). b, Cardiac glycogen concentrations in hearts of fed and fasted mice (n = 10, 14, 15, and 14, respectively). c, Plasma TAG from fed or fasted mice (n = 22, 15, 16, and 14, respectively). d-i, Cardiac gene expression for natriuretic peptides and PPARα-target and fatty acid metabolism genes (n = 8, 9, 7, and 6, respectively). Data are presented as mean ± s.e.m. within dot plot. Each symbol on dot plot represents an individual sample. Two-way ANOVA with Tukey’s multiple comparisons test.

Extended Data Fig. 8 Ketogenic diet reverses heart failure in CS-MPC2−/− mice.

a-h, Echocardiography measurements before and after 3 weeks of LF or KD feeding in 16-week-old CS-MPC2−/− mice with established heart failure (n = 3 LF, 5 KD). Data are presented as PRE-POST. Each data point represents an individual mouse. Paired two-tailed student’s t-test for PRE vs. POST. Unpaired two-tailed student’s t-test for LF vs. KD.

Supplementary information

Reporting Summary

Supplementary Tables

Supplementary Tables 1–4

Supplementary Video 1

Cardiac dysfunction and remodelling prevented by ketogenic diet.

Supplementary Video 2

Cardiac dysfunction improved by high-fat diets.

Supplementary Video 3

Three weeks of ketogenic diet reverses heart failure in CS-MPC2−/− mice.

Source data

Source Data Fig. 1

Unprocessed western blots.

Source Data Fig. 2

Unprocessed western blots.

Source Data Fig. 3

Unprocessed western blots.

Source Data Fig. 4

Unprocessed western blots.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McCommis, K.S., Kovacs, A., Weinheimer, C.J. et al. Nutritional modulation of heart failure in mitochondrial pyruvate carrier–deficient mice. Nat Metab 2, 1232–1247 (2020). https://doi.org/10.1038/s42255-020-00296-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-020-00296-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing