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Cluntun AA, Badolia R, Lettlova S, et al. The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell Metab. 2020;33(3):629-648.e10doi: 10.1016/j.cmet.2020.12.003.
Cluntun, A. A., Badolia, R., Lettlova, S., Parnell, K. M., Shankar, T. S., Diakos, N. A., Olson, K. A., Taleb, I., Tatum, S. M., Berg, J. A., Cunningham, C. N., Van Ry, T., Bott, A. J., Krokidi, A. T., Fogarty, S., Skedros, S., Swiatek, W. I., Yu, X., Luo, B., Merx, S., Navankasattusas, S., Cox, J. E., Ducker, G. S., Holland, W. L., McKellar, S. H., Rutter, J., & Drakos, S. G. (2021). The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell metabolism, 33(3), 629-648.e10. https://doi.org/10.1016/j.cmet.2020.12.003
Cluntun, Ahmad A, et al. "The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure." Cell metabolism vol. 33,3 (2021): 629-648.e10. doi: https://doi.org/10.1016/j.cmet.2020.12.003
Cluntun AA, Badolia R, Lettlova S, Parnell KM, Shankar TS, Diakos NA, Olson KA, Taleb I, Tatum SM, Berg JA, Cunningham CN, Van Ry T, Bott AJ, Krokidi AT, Fogarty S, Skedros S, Swiatek WI, Yu X, Luo B, Merx S, Navankasattusas S, Cox JE, Ducker GS, Holland WL, McKellar SH, Rutter J, Drakos SG. The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell Metab. 2021 Mar 02;33(3):629-648.e10. doi: 10.1016/j.cmet.2020.12.003. Epub 2020 Dec 16. PMID: 33333007; PMCID: PMC7933116.
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Cell Metab. 2021 Mar 02;33(3):629-648.e10. doi: 10.1016/j.cmet.2020.12.003. Epub 2020 Dec 16.

The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure.

Cell metabolism

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

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: [email protected].
  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: [email protected].

PMID: 33333007 PMCID: PMC7933116 DOI: 10.1016/j.cmet.2020.12.003

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.

Copyright © 2020 Elsevier Inc. All rights reserved.

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

Conflict of interest statement

Declaration of interests The University of Utah has filed a patent related to the mitochondrial pyruvate carrier, of which J.R. is listed as co-inventor. J.R. is a founder of Vettore Biosciences and a

References

  1. Nucleic Acids Res. 2007 Jul;35(Web Server issue):W193-200 - PubMed
  2. Am J Physiol Endocrinol Metab. 2003 May;284(5):E855-62 - PubMed
  3. J Am Coll Cardiol. 2016 Oct 18;68(16):1741-1752 - PubMed
  4. Cell. 2015 Jul 30;162(3):552-63 - PubMed
  5. J Card Fail. 2012 Oct;18(10):755-61 - PubMed
  6. Cardiovasc Res. 2017 Mar 15;113(4):411-421 - PubMed
  7. Cancer Res. 2015 Jan 1;75(1):171-80 - PubMed
  8. Card Fail Rev. 2017 Apr;3(1):7-11 - PubMed
  9. J Mol Cell Cardiol. 1997 Oct;29(10):2771-8 - PubMed
  10. Cell Rep. 2020 Sep 1;32(9):108087 - PubMed
  11. Nat Commun. 2018 Jul 26;9(1):2935 - PubMed
  12. Science. 2015 Jan 23;347(6220):1260419 - PubMed
  13. Nat Rev Cardiol. 2018 Aug;15(8):457-470 - PubMed
  14. Bioinformatics. 2014 Apr 1;30(7):923-30 - PubMed
  15. Arterioscler Thromb Vasc Biol. 2016 Apr;36(4):636-46 - PubMed
  16. Nat Rev Cardiol. 2017 Apr;14(4):238-250 - PubMed
  17. J Am Heart Assoc. 2019 Jun 18;8(12):e012673 - PubMed
  18. J Clin Invest. 1988 Dec;82(6):2017-25 - PubMed
  19. Nat Cell Biol. 2017 Sep;19(9):1027-1036 - PubMed
  20. J Mol Cell Cardiol. 1992 Jul;24(7):669-81 - PubMed
  21. Cell Metab. 2016 Nov 8;24(5):716-727 - PubMed
  22. Med Sci Sports Exerc. 2000 Apr;32(4):756-63 - PubMed
  23. Am J Med Sci. 1999 Jul;318(1):36-42 - PubMed
  24. Cell. 2018 Oct 4;175(2):502-513.e13 - PubMed
  25. Am Heart J. 2001 Oct;142(4):704-13 - PubMed
  26. Cell Metab. 2015 Oct 6;22(4):682-94 - PubMed
  27. J Clin Invest. 1985 Nov;76(5):1819-27 - PubMed
  28. Mol Metab. 2017 Nov;6(11):1468-1479 - PubMed
  29. J Clin Invest. 1993 Jul;92(1):398-403 - PubMed
  30. Mol Cancer Ther. 2018 Dec;17(12):2746-2755 - PubMed
  31. Mol Med. 2018 Mar 15;24(1):3 - PubMed
  32. Genome Biol. 2014;15(12):550 - PubMed
  33. Circ Res. 2017 Sep 15;121(7):731-748 - PubMed
  34. J Am Coll Cardiol. 2013 May 14;61(19):1985-94 - PubMed
  35. Circulation. 2008 Sep 30;118(14 Suppl):S94-105 - PubMed
  36. Curr Opin Biotechnol. 2015 Aug;34:189-201 - PubMed
  37. In Vitro Cell Dev Biol Anim. 2011 Feb;47(2):125-31 - PubMed
  38. J Am Coll Cardiol. 1994 Mar 1;23(3):586-90 - PubMed
  39. Cell. 2015 Jul 30;162(3):540-51 - PubMed
  40. Nature. 2020 Sep;585(7825):357-362 - PubMed
  41. Cell Metab. 2020 Feb 4;31(2):284-300.e7 - PubMed
  42. Nat Protoc. 2011 Jun;6(6):743-60 - PubMed
  43. JACC Basic Transl Sci. 2017 Jun;2(3):335-340 - PubMed
  44. Circ Res. 2001 Jul 6;89(1):20-5 - PubMed
  45. Nat Cell Biol. 2017 Sep;19(9):1017-1026 - PubMed
  46. Front Cardiovasc Med. 2018 Jun 06;5:68 - PubMed
  47. Circ Heart Fail. 2016 Jul;9(7): - PubMed
  48. Cell Physiol Biochem. 2013;32(3):663-74 - PubMed
  49. Cell. 2009 Aug 21;138(4):628-44 - PubMed
  50. PLoS Comput Biol. 2020 Jan 31;16(1):e1007625 - PubMed
  51. Elife. 2019 Jul 18;8: - PubMed
  52. Biochem J. 1998 Jan 15;329 ( Pt 2):321-8 - PubMed
  53. Mol Aspects Med. 2013 Apr-Jun;34(2-3):465-84 - PubMed
  54. Sci Transl Med. 2018 Mar 28;10(434): - PubMed
  55. Oxid Med Cell Longev. 2019 Feb 7;2019:4532592 - PubMed
  56. PLoS One. 2015 Jun 29;10(6):e0129303 - PubMed
  57. Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3530-3535 - PubMed
  58. Cardiovasc Res. 2011 May 1;90(2):234-42 - PubMed
  59. Am J Physiol. 1994 Aug;267(2 Pt 2):H742-50 - PubMed
  60. N Engl J Med. 2003 May 15;348(20):2007-18 - PubMed
  61. Cancer Metab. 2015 Sep 23;3:10 - PubMed
  62. Eur J Appl Physiol. 2001 Nov;86(1):6-11 - PubMed
  63. Bioinformatics. 2016 Oct 1;32(19):3047-8 - PubMed
  64. Pharmacol Rev. 1999 Sep;51(3):465-501 - PubMed
  65. Anal Biochem. 2018 Jul 1;552:50-59 - PubMed
  66. J Mol Cell Cardiol. 2001 Jun;33(6):1065-89 - PubMed
  67. EMBO J. 2000 Aug 1;19(15):3896-904 - PubMed
  68. Lancet. 2017 Oct 28;390(10106):1981-1995 - PubMed
  69. J Cardiovasc Med (Hagerstown). 2016 Jan;17(1):37-43 - PubMed
  70. Circ Res. 2013 Aug 16;113(5):603-16 - PubMed
  71. Nat Chem Biol. 2005 Dec;1(7):371-6 - PubMed
  72. J Clin Invest. 2018 Aug 31;128(9):3716-3726 - PubMed
  73. Braz J Med Biol Res. 2018 Oct 04;51(11):e7660 - PubMed
  74. J Appl Physiol (1985). 2002 Apr;92(4):1573-84 - PubMed
  75. Nucleic Acids Res. 2018 Jul 2;46(W1):W486-W494 - PubMed
  76. Bioinformatics. 2013 Jan 1;29(1):15-21 - PubMed
  77. Free Radic Res. 1997 Jan;26(1):19-35 - PubMed
  78. Arch Toxicol. 2015 Sep;89(9):1401-38 - PubMed
  79. J Appl Physiol (1985). 2000 Jul;89(1):169-75 - PubMed
  80. Am J Med. 1953 Sep;15(3):284-96 - PubMed
  81. J Cell Biol. 1966 Jul;30(1):23-38 - PubMed
  82. Nature. 2017 Nov 2;551(7678):115-118 - PubMed
  83. Cell. 2016 Aug 25;166(5):1324-1337.e11 - PubMed
  84. Circ Res. 2020 Jan 17;126(2):182-196 - PubMed
  85. J Transl Med. 2020 Sep 4;18(1):341 - PubMed
  86. Circulation. 2017 Aug 8;136(6):e137-e161 - PubMed
  87. Front Cardiovasc Med. 2018 Mar 06;5:17 - PubMed
  88. Clin Res Cardiol. 2018 Aug;107(Suppl 2):114-119 - PubMed
  89. Science. 2012 Jul 6;337(6090):96-100 - PubMed
  90. Oncogene. 2014 Aug 28;33(35):4433-41 - PubMed
  91. Nat Protoc. 2017 Oct;12(10):2215-2231 - PubMed
  92. Circulation. 2011 Feb 1;123(4):381-90 - PubMed
  93. Science. 2015 Dec 4;350(6265):aad0116 - PubMed
  94. Cell Metab. 2015 Oct 6;22(4):669-81 - PubMed
  95. PLoS One. 2015 May 21;10(5):e0127843 - PubMed
  96. Cardiovasc Res. 2018 Jul 1;114(8):1132-1144 - PubMed
  97. J Biol Chem. 1998 Jun 26;273(26):15920-6 - PubMed
  98. Cell Rep. 2019 Oct 1;29(1):76-88.e7 - PubMed
  99. J Am Coll Cardiol. 2016 Oct 4;68(14):1540-53 - PubMed
  100. Circ Res. 1995 Oct;77(4):773-83 - PubMed
  101. Circulation. 2020 Jul 21;142(3):259-274 - PubMed
  102. Cell Metab. 2014 Mar 4;19(3):357-72 - PubMed
  103. J Pharmacol Toxicol Methods. 2007 Nov-Dec;56(3):317-22 - PubMed
  104. Mol Cell Biochem. 1995 May 24;146(2):147-55 - PubMed
  105. N Engl J Med. 2006 Nov 2;355(18):1873-84 - PubMed
  106. Am J Cardiol. 1999 Jun 17;83(12A):64H-69H - PubMed
  107. J Biol Chem. 2018 Aug 3;293(31):12199-12208 - PubMed
  108. Circ Res. 1975 Nov;37(5):527-33 - PubMed
  109. JACC Basic Transl Sci. 2016 Oct;1(6):432-444 - PubMed
  110. iScience. 2019 Dec 20;22:507-518 - PubMed
  111. J Physiol. 2009 May 1;587(Pt 9):2087-99 - PubMed
  112. Cell Rep. 2018 Dec 11;25(11):3047-3058.e4 - PubMed
  113. Nat Commun. 2015 Feb 17;6:6259 - PubMed

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