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.

  • Review Article
  • Published:

Metabolite signaling in the heart

Nature Cardiovascular Research volume 2, pages 504–516 (2023)Cite this article

Subjects

Abstract

The heart is the most metabolically active organ in the body, sustaining a continuous and high flux of nutrient catabolism via oxidative phosphorylation. The nature and relative contribution of these fuels have been studied extensively for decades. By contrast, less attention has been placed on how intermediate metabolites generated from this catabolism affect intracellular signaling. Numerous metabolites, including intermediates of glycolysis and the tricarboxylic acid (TCA) cycle, nucleotides, amino acids, fatty acids and ketones, are increasingly appreciated to affect signaling in the heart, via various mechanisms ranging from protein–metabolite interactions to modifying epigenetic marks. We review here the current state of knowledge of intermediate metabolite signaling in the heart.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Metabolic sensors sense metabolite concentrations.
Fig. 2: TCA intermediates as signals in the heart.
Fig. 3: Signaling by glycolytic intermediates and offshoots of glycolysis.
Fig. 4: Amino acids as signals in the heart.

Similar content being viewed by others

References

  1. Lopaschuk, G. D., Karwi, Q. G., Tian, R., Wende, A. R. & Abel, E. D. Cardiac energy metabolism in heart failure. Circ. Res. 128, 1487–1513 (2021). Excellent recent review on intermediate metabolism in the heart.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sullivan, L. B., Gui, D. Y. & Vander Heiden, M. G. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat. Rev. Cancer 16, 680–693 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785–789 (1963). Classic paper describing the antagonistic relationship between fatty acid and carbohydrate use in the heart.

    Article  CAS  PubMed  Google Scholar 

  4. Hue, L. & Taegtmeyer, H. The Randle cycle revisited: a new head for an old hat. Am. J. Physiol. Endocrinol. Metab. 297, E578–E591 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Alrob, O. A. et al. Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling. Cardiovasc. Res. 103, 485–497 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gibala, M. J., MacLean, D. A., Graham, T. E. & Saltin, B. Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise. Am. J. Physiol. 275, E235–E242 (1998).

    CAS  PubMed  Google Scholar 

  7. Bartman, C. R., TeSlaa, T. & Rabinowitz, J. D. Quantitative flux analysis in mammals. Nat. Metab. 3, 896–908 (2021). Comprehensive and quantitative analyses of whole-body fuel flux in mice.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Vendelin, M. & Birkedal, R. Anisotropic diffusion of fluorescently labeled ATP in rat cardiomyocytes determined by raster image correlation spectroscopy. Am. J. Physiol. Cell Physiol. 295, C1302–C1315 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Norris, J. L. & Caprioli, R. M. Analysis of tissue specimens by matrix-assisted laser desorption/ionization imaging mass spectrometry in biological and clinical research. Chem. Rev. 113, 2309–2342 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gilmore, I. S., Heiles, S. & Pieterse, C. L. Metabolic imaging at the single-cell scale: recent advances in mass spectrometry imaging. Annu. Rev. Anal. Chem. 12, 201–224 (2019).

    Article  CAS  Google Scholar 

  11. Sahlin, K., Katz, A. & Broberg, S. Tricarboxylic acid cycle intermediates in human muscle during prolonged exercise. Am. J. Physiol. 259, C834–C841 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Flam, E. et al. Integrated landscape of cardiac metabolism in end-stage human non-ischemic dilated cardiomyopathy. Nat. Cardiovasc. Res. 1, 817–829 (2022).

    PubMed  Google Scholar 

  13. Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014). Paradigm-shifting demonstration of the key role succinate that plays in cardiac I/R injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Martin, J. L. et al. Succinate accumulation drives ischaemia–reperfusion injury during organ transplantation. Nat. Metab. 1, 966–974 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Milliken, A. S., Nadtochiy, S. M. & Brookes, P. S. Inhibiting succinate release worsens cardiac reperfusion injury by enhancing mitochondrial reactive oxygen species generation. J. Am. Heart Assoc. 11, e026135 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Murphy, M. P. & Chouchani, E. T. Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel. Nat. Chem. Biol. 18, 461–469 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jr Kaelin, W. G. & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Moslehi, J. et al. Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation 122, 1004–1016 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Knutson, A. K., Williams, A. L., Boisvert, W. A. & Shohet, R. V. HIF in the heart: development, metabolism, ischemia, and atherosclerosis. J. Clin. Invest. 131, e137557 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sano, M. et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446, 444–448 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Koivunen, P. et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 282, 4524–4532 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Dodd, M. S. et al. Fatty acids prevent hypoxia-inducible factor-1α signaling through decreased succinate in diabetes. JACC Basic Transl. Sci. 3, 485–498 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Prag, H. A. et al. Mechanism of succinate efflux upon reperfusion of the ischaemic heart. Cardiovasc. Res. 117, 1188–1201 (2021).

    Article  CAS  PubMed  Google Scholar 

  24. Pepin, M. E. et al. DNA methylation reprograms cardiac metabolic gene expression in end-stage human heart failure. Am. J. Physiol. Heart Circ. Physiol. 317, H674–H684 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Haas, J. et al. Alterations in cardiac DNA methylation in human dilated cardiomyopathy. EMBO Mol. Med. 5, 413–429 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xiao, D. et al. Inhibition of DNA methylation reverses norepinephrine-induced cardiac hypertrophy in rats. Cardiovasc. Res. 101, 373–382 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Kaneda, R. et al. Genome-wide histone methylation profile for heart failure. Genes Cells 14, 69–77 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Rosa-Garrido, M., Chapski, D. J. & Vondriska, T. M. Epigenomes in cardiovascular disease. Circ. Res. 122, 1586–1607 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang, Q. J. et al. The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J. Clin. Invest. 121, 2447–2456 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kranendijk, M., Struys, E. A., Salomons, G. S., Van der Knaap, M. S. & Jakobs, C. Progress in understanding 2-hydroxyglutaric acidurias. J. Inherit. Metab. Dis. 35, 571–587 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). Discovery of neomorphic mutations in IDH1 that promote enzymatic production of 2-hydroglutarate, which in turn powerfully inhibits various dioxygenases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Karlstaedt, A. et al. Oncometabolite d-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart. Proc. Natl Acad. Sci. USA 113, 10436–10441 (2016). Established connection between 2-hydroxyglutarate and cardiac dysfunction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Latini, A. et al. Mitochondrial energy metabolism is markedly impaired by d-2-hydroxyglutaric acid in rat tissues. Mol. Genet. Metab. 86, 188–199 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Diotallevi, M., Ayaz, F., Nicol, T. & Crabtree, M. J. Itaconate as an inflammatory mediator and therapeutic target in cardiovascular medicine. Biochem. Soc. Trans. 49, 2189–2198 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Murphy, M. P. & O’Neill, L. A. J. Krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers. Cell 174, 780–784 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Michelucci, A. et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc. Natl Acad. Sci. USA 110, 7820–7825 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu, R. et al. Aconitate decarboxylase 1 is a mediator of polymicrobial sepsis. Sci. Transl. Med. 14, eabo2028 (2022).

    Article  CAS  PubMed  Google Scholar 

  42. Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis. Nature 556, 501–504 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Swain, A. et al. Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages. Nat. Metab. 2, 594–602 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Song, H. et al. Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2. EBioMedicine 57, 102832 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Qin, W. et al. S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate. Nat. Chem. Biol. 15, 983–991 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Nakkala, J. R. et al. Dimethyl itaconate-loaded nanofibers rewrite macrophage polarization, reduce inflammation, and enhance repair of myocardic infarction. Small 17, e2006992 (2021).

    Article  PubMed  Google Scholar 

  48. Shan, Q. et al. Protective effects of dimethyl itaconate in mice acute cardiotoxicity induced by doxorubicin. Biochem. Biophys. Res. Commun. 517, 538–544 (2019).

    Article  CAS  PubMed  Google Scholar 

  49. Ashrafian, H. et al. Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metab. 15, 361–371 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ali, H. R. et al. Defining decreased protein succinylation of failing human cardiac myofibrils in ischemic cardiomyopathy. J. Mol. Cell. Cardiol. 138, 304–317 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Taegtmeyer, H., Roberts, A. F. & Raine, A. E. Energy metabolism in reperfused heart muscle: metabolic correlates to return of function. J. Am. Coll. Cardiol. 6, 864–870 (1985).

    Article  CAS  PubMed  Google Scholar 

  53. Sen, S. et al. Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. J. Am. Heart Assoc. 2, e004796 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Shioi, T. et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation 107, 1664–1670 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Sharma, S., Guthrie, P. H., Chan, S. S., Haq, S. & Taegtmeyer, H. Glucose phosphorylation is required for insulin-dependent mTOR signalling in the heart. Cardiovasc. Res. 76, 71–80 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Roberts, D. J., Tan-Sah, V. P., Ding, E. Y., Smith, J. M. & Miyamoto, S. Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol. Cell 53, 521–533 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Miyamoto, S., Murphy, A. N. & Brown, J. H. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 15, 521–529 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Sun, L., Shukair, S., Naik, T. J., Moazed, F. & Ardehali, H. Glucose phosphorylation and mitochondrial binding are required for the protective effects of hexokinases I and II. Mol. Cell. Biol. 28, 1007–1017 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  CAS  PubMed  Google Scholar 

  60. Olson, A. K., Bouchard, B., Zhu, W. Z., Chatham, J. C. & Des Rosiers, C. First characterization of glucose flux through the hexosamine biosynthesis pathway (HBP) in ex vivo mouse heart. J. Biol. Chem. 295, 2018–2033 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lunde, I. G. et al. Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure. Physiol. Genomics 44, 162–172 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Prakoso, D. et al. Fine-tuning the cardiac O-GlcNAcylation regulatory enzymes governs the functional and structural phenotype of the diabetic heart. Cardiovasc. Res. 118, 212–225 (2021).

  63. Wang, Z. V. et al. Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 156, 1179–1192 (2014). Initial demonstration of a link between the endoplasmic reticulum stress response and glycolytic side programs, including the HBP, promoting cardiac hypertrophy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tran, D. H. et al. Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling. Nat. Commun. 11, 1771 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gelinas, R. et al. AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation. Nat. Commun. 9, 374 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Erickson, J. R. et al. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature 502, 372–376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kronlage, M. et al. O-GlcNAcylation of histone deacetylase 4 protects the diabetic heart from failure. Circulation 140, 580–594 (2019).

    Article  CAS  PubMed  Google Scholar 

  68. Medford, H. M., Porter, K. & Marsh, S. A. Immediate effects of a single exercise bout on protein O-GlcNAcylation and chromatin regulation of cardiac hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 305, H114–H123 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hegyi, B. et al. CaMKII serine 280 O-GlcNAcylation links diabetic hyperglycemia to proarrhythmia. Circ. Res. 129, 98–113 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lu, S. et al. Hyperglycemia acutely increases cytosolic reactive oxygen species via O-linked GlcNAcylation and CaMKII activation in mouse ventricular myocytes. Circ. Res. 126, e80–e96 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chatham, J. C., Zhang, J. & Wende, A. R. Role of O-linked N-acetylglucosamine protein modification in cellular (patho)physiology. Physiol. Rev. 101, 427–493 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Lauzier, B. et al. Metabolic effects of glutamine on the heart: anaplerosis versus the hexosamine biosynthetic pathway. J. Mol. Cell. Cardiol. 55, 92–100 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Lehmann, L. H. et al. A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat. Med. 24, 62–72 (2018).

    Article  CAS  PubMed  Google Scholar 

  74. Schalkwijk, C. G. & Stehouwer, C. D. A. Methylglyoxal, a highly reactive dicarbonyl compound, in diabetes, its vascular complications, and other age-related diseases. Physiol. Rev. 100, 407–461 (2020).

    Article  CAS  PubMed  Google Scholar 

  75. Bollong, M. J. et al. A metabolite-derived protein modification integrates glycolysis with KEAP1–NRF2 signalling. Nature 562, 600–604 (2018). Demonstration of how methyl glyoxylate, the most reactive known glycolytic metabolite and leading cause of AGEs, triggers a cellular hormetic response via the KEAP–NRF2 pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Papadaki, M. et al. Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function. JCI Insight 3, e121264 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Tian, C. et al. Reactive carbonyl species and their roles in sarcoplasmic reticulum Ca2+ cycling defect in the diabetic heart. Heart Fail. Rev. 19, 101–112 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Thangarajah, H. et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc. Natl Acad. Sci. USA 106, 13505–13510 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bento, C. F. et al. The chaperone-dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal. PLoS ONE 5, e15062 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ramasamy, R. & Schmidt, A. M. Receptor for advanced glycation end products (RAGE) and implications for the pathophysiology of heart failure. Curr. Heart Fail. Rep. 9, 107–116 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shimizu, Y. et al. Role of DJ-1 in modulating glycative stress in heart failure. J. Am. Heart Assoc. 9, e014691 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Qi, D. & Young, L. H. AMPK: energy sensor and survival mechanism in the ischemic heart. Trends Endocrinol. Metab. 26, 422–429 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Dyck, J. R. & Lopaschuk, G. D. AMPK alterations in cardiac physiology and pathology: enemy or ally? J. Physiol. 574, 95–112 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang, J., Gareri, C. & Rockman, H. A. G-protein-coupled receptors in heart disease. Circ. Res. 123, 716–735 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Downey, J. M., Davis, A. M. & Cohen, M. V. Signaling pathways in ischemic preconditioning. Heart Fail. Rev. 12, 181–188 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Salazar, N. C., Chen, J. & Rockman, H. A. Cardiac GPCRs: GPCR signaling in healthy and failing hearts. Biochim. Biophys. Acta 1768, 1006–1018 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bak, M. I. & Ingwall, J. S. Acidosis during ischemia promotes adenosine triphosphate resynthesis in postischemic rat heart. In vivo regulation of 5′-nucleotidase. J. Clin. Invest. 93, 40–49 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Corriden, R. & Insel, P. A. Basal release of ATP: an autocrine–paracrine mechanism for cell regulation. Sci. Signal. 3, re1 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Eltzschig, H. K. et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J. Exp. Med. 198, 783–796 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Burnstock, G. Purinergic signaling in the cardiovascular system. Circ. Res. 120, 207–228 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Li, S. et al. Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair. J. Clin. Invest. 132, e149711 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Katsyuba, E., Romani, M., Hofer, D. & Auwerx, J. NAD+ homeostasis in health and disease. Nat. Metab. 2, 9–31 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Canto, C., Menzies, K. J. & Auwerx, J. NAD+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 22, 31–53 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Horton, J. L. et al. Mitochondrial protein hyperacetylation in the failing heart. JCI Insight 2, e84897 (2016).

    PubMed  Google Scholar 

  95. Lee, C. F. et al. Normalization of NAD+ redox balance as a therapy for heart failure. Circulation 134, 883–894 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Diguet, N. et al. Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation 137, 2256–2273 (2018).

    Article  CAS  PubMed  Google Scholar 

  97. Emily Flam, C. J. et al. Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy. Nat. Cardiovasc. Res. 1, 817–829 (2022).

    PubMed  Google Scholar 

  98. Martin, A. S. et al. Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model. JCI Insight 2, e93885 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Davidson, M. T. et al. Extreme acetylation of the cardiac mitochondrial proteome does not promote heart failure. Circ. Res. 127, 1094–1108 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Walker, M. A. et al. Acetylation of muscle creatine kinase negatively impacts high-energy phosphotransfer in heart failure. JCI Insight 6, e144301 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Walker, M. A. & Tian, R. Raising NAD in heart failure: time to translate? Circulation 137, 2274–2277 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Walker, M. A. & Tian, R. NAD(H) in mitochondrial energy transduction: implications for health and disease. Curr. Opin. Physiol. 3, 101–109 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Hui, S. et al. Quantitative fluxomics of circulating metabolites. Cell Metab. 32, 676–688 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Murashige, D. et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science 370, 364–368 (2020). A comprehensive evaluation of human cardiac fuel use, using arterial and coronary sinus blood sampling and quantifying global metabolites with mass spectrometry.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lombardi, A. A. et al. Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation. Nat. Commun. 10, 4509 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Gibb, A. A. et al. Glutaminolysis is essential for myofibroblast persistence and in vivo targeting reverses fibrosis and cardiac dysfunction in heart failure. Circulation 145, 1625–1628 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gibb, A. A., Ploesch, T., Arany, Z. & Elrod, J. W. Genetic deletion of cardiomyocyte glutamine synthetase in a model of HF hints at cardiomyocyte to fibroblast metabolic crosstalk mediating fibrosis. Circulation 144, A14413 (2021).

  108. Sun, H. et al. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133, 2038–2049 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lai, L. et al. Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach. Circ. Heart Fail. 7, 1022–1031 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wang, W. et al. Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 311, H1160–H1169 (2016).

    Article  PubMed  Google Scholar 

  111. Li, T. et al. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia–reperfusion injury. Cell Metab. 25, 374–385 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chen, M. et al. Therapeutic effect of targeting branched-chain amino acid catabolic flux in pressure-overload induced heart failure. J. Am. Heart Assoc. 8, e011625 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Walejko, J. M. et al. Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart. Nat. Commun. 12, 1680 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Murashige, D. et al. Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure. Cell Metab. 34, 1749–1764 (2022).

    Article  CAS  PubMed  Google Scholar 

  115. Previs, M. J. et al. Defects in the proteome and metabolome in human hypertrophic cardiomyopathy. Circ. Heart Fail. 15, e009521 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Montaigne, D., Butruille, L. & Staels, B. PPAR control of metabolism and cardiovascular functions. Nat. Rev. Cardiol. 18, 809–823 (2021).

    Article  CAS  PubMed  Google Scholar 

  118. Madrazo, J. A. & Kelly, D. P. The PPAR trio: regulators of myocardial energy metabolism in health and disease. J. Mol. Cell. Cardiol. 44, 968–975 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Karamanlidis, G. et al. Defective DNA replication impairs mitochondrial biogenesis in human failing hearts. Circ. Res. 106, 1541–1548 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Levelt, E. et al. Relationship between left ventricular structural and metabolic remodeling in type 2 diabetes. Diabetes 65, 44–52 (2016).

    Article  CAS  PubMed  Google Scholar 

  121. Rijzewijk, L. J. et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J. Am. Coll. Cardiol. 52, 1793–1799 (2008).

    Article  PubMed  Google Scholar 

  122. Leggat, J., Bidault, G. & Vidal-Puig, A. Lipotoxicity: a driver of heart failure with preserved ejection fraction? Clin. Sci. 135, 2265–2283 (2021).

    Article  CAS  Google Scholar 

  123. Lehman, J. J. & Kelly, D. P. Transcriptional activation of energy metabolic switches in the developing and hypertrophied heart. Clin. Exp. Pharmacol. Physiol. 29, 339–345 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Riquelme, C. A. et al. Fatty acids identified in the Burmese python promote beneficial cardiac growth. Science 334, 528–531 (2012). Dramatic demonstration of the ability of circulating metabolites, in this case, fatty acids, to promote cardiac hypertrophy, in this case, in the Burmese python of a once-in-a-month meal.

    Article  Google Scholar 

  125. Linder, M. E. & Deschenes, R. J. Palmitoylation: policing protein stability and traffic. Nat. Rev. Mol. Cell Biol. 8, 74–84 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Essandoh, K., Philippe, J. M., Jenkins, P. M. & Brody, M. J. Palmitoylation: a fatty regulator of myocardial electrophysiology. Front. Physiol. 11, 108 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Schulze, P. C., Drosatos, K. & Goldberg, I. J. Lipid use and misuse by the heart. Circ. Res. 118, 1736–1751 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Harada, M. et al. Diacylglycerol kinase ζ attenuates pressure overload-induced cardiac hypertrophy. Circ. J. 71, 276–282 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Chokshi, A. et al. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation 125, 2844–2853 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hadas, Y. et al. Altering sphingolipid metabolism attenuates cell death and inflammatory response after myocardial infarction. Circulation 141, 916–930 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ji, R. et al. Increased de novo ceramide synthesis and accumulation in failing myocardium. JCI Insight 2, e82922 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Park, T. S. et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J. Lipid Res. 49, 2101–2112 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Means, C. K. & Brown, J. H. Sphingosine-1-phosphate receptor signalling in the heart. Cardiovasc. Res. 82, 193–200 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lopaschuk, G. D., Ussher, J. R., Folmes, C. D., Jaswal, J. S. & Stanley, W. C. Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 90, 207–258 (2010). Definitive review on fatty acid metabolism in the heart.

    Article  CAS  PubMed  Google Scholar 

  135. Choi, R. H., Tatum, S. M., Symons, J. D., Summers, S. A. & Holland, W. L. Ceramides and other sphingolipids as drivers of cardiovascular disease. Nat. Rev. Cardiol. 18, 701–711 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Pinckard, K. M. et al. A novel endocrine role for the BAT-released lipokine 12,13-diHOME to mediate cardiac function. Circulation 143, 145–159 (2021). Identification of a new modified fatty acid, diHOME, released by adipose tissue, that contributes to mediating the cardiac response to exercise.

    Article  CAS  PubMed  Google Scholar 

  137. Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Puchalska, P. & Crawford, P. A. Metabolic and signaling roles of ketone bodies in health and disease. Annu. Rev. Nutr. 41, 49–77 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Byrne, N. J. et al. Chronically elevating circulating ketones can reduce cardiac inflammation and blunt the development of heart failure. Circ. Heart Fail. 13, e006573 (2020).

    Article  CAS  PubMed  Google Scholar 

  141. Newman, J. C. & Verdin, E. β-hydroxybutyrate: a signaling metabolite. Annu. Rev. Nutr. 37, 51–76 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Kimura, I. et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl Acad. Sci. USA 108, 8030–8035 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Rezq, S. & Abdel-Rahman, A. A. Central GPR109A activation mediates glutamate-dependent pressor response in conscious rats. J. Pharmacol. Exp. Ther. 356, 456–465 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Deng, Y. et al. Targeting mitochondria–inflammation circuit by β-hydroxybutyrate mitigates HFpEF. Circ. Res. 128, 232–245 (2021).

    Article  CAS  PubMed  Google Scholar 

  146. Byrne, N. J. et al. Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure. Circ. Heart Fail. 13, e006277 (2020).

    Article  CAS  PubMed  Google Scholar 

  147. Youm, Y. H. et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Cowie, M. R. & Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat. Rev. Cardiol. 7, 761–772 (2020).

    Article  Google Scholar 

  149. Philippaert, K. et al. Cardiac late sodium channel current is a molecular target for the sodium/glucose cotransporter 2 inhibitor empagliflozin. Circulation 143, 2188–2204 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Xie, Z. et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol. Cell 62, 194–206 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Chong, D. et al. Neonatal ketone body elevation regulates postnatal heart development by promoting cardiomyocyte mitochondrial maturation and metabolic reprogramming. Cell Discov. 8, 106 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wu, L. F. et al. Global profiling of protein lysine malonylation in mouse cardiac hypertrophy. J. Proteomics 266, 104667 (2022).

    Article  CAS  PubMed  Google Scholar 

  153. Orsak, T. et al. Revealing the allosterome: systematic identification of metabolite–protein interactions. Biochemistry 51, 225–232 (2012).

    Article  CAS  PubMed  Google Scholar 

  154. Hicks, K. G. et al. Protein–metabolite interactomics reveals novel regulation of carbohydrate metabolism. Preprint at bioRxiv https://doi.org/10.1101/2021.08.28.458030 (2021).

  155. Duncan, K. D., Fyrestam, J. & Lanekoff, I. Advances in mass spectrometry based single-cell metabolomics. Analyst 144, 782–793 (2019).

    Article  CAS  PubMed  Google Scholar 

  156. Husted, A. S., Trauelsen, M., Rudenko, O., Hjorth, S. A. & Schwartz, T. W. GPCR-mediated signaling of metabolites. Cell Metab. 25, 777–796 (2017).

    Article  CAS  PubMed  Google Scholar 

  157. Hakak, Y., Shrestha, D., Goegel, M. C., Behan, D. P. & Chalmers, D. T. Global analysis of G-protein-coupled receptor signaling in human tissues. FEBS Lett. 550, 11–17 (2003).

    Article  CAS  PubMed  Google Scholar 

  158. Olenchock, B. A. et al. EGLN1 inhibition and rerouting of α-ketoglutarate suffice for remote ischemic protection. Cell 164, 884–895 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Wyant, G. A. et al. Mitochondrial remodeling and ischemic protection by G protein-coupled receptor 35 agonists. Science 377, 621–629 (2022). Identification of a tryptophan metabolite that mediates the ability of skeletal muscle ischemic episodes to protect subsequent cardiac ischemia, a phenomenon known as distal ischemic preconditioning.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Divorty, N., Milligan, G., Graham, D. & Nicklin, S. A. The orphan receptor GPR35 contributes to angiotensin II-induced hypertension and cardiac dysfunction in mice. Am. J. Hypertens. 31, 1049–1058 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Li, H. et al. Novel role of GPR35 (G-protein-coupled receptor 35) in the regulation of endothelial cell function and blood pressure. Hypertension 78, 816–830 (2021).

    Article  CAS  PubMed  Google Scholar 

  162. He, W. et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193 (2004).

    Article  CAS  PubMed  Google Scholar 

  163. Aguiar, C. J. et al. Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation. Cell Commun. Signal. 12, 78 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Yang, L. et al. Triggering the succinate receptor GPR91 enhances pressure overload-induced right ventricular hypertrophy. Int. J. Clin. Exp. Pathol. 7, 5415–5428 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Keiran, N. et al. SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity. Nat. Immunol. 20, 581–592 (2019).

    Article  CAS  PubMed  Google Scholar 

  166. Serena, C. et al. Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota. ISME J. 12, 1642–1657 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Cuspidi, C., Rescaldani, M., Sala, C. & Grassi, G. Left-ventricular hypertrophy and obesity: a systematic review and meta-analysis of echocardiographic studies. J. Hypertens. 32, 16–25 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Briscoe, C. P. et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J. Biol. Chem. 278, 11303–11311 (2003).

    Article  CAS  PubMed  Google Scholar 

  169. Umar, S. et al. Free fatty acid receptor G-protein-coupled receptor 40 mediates lipid emulsion-induced cardioprotection. Anesthesiology 129, 154–162 (2018).

    Article  CAS  PubMed  Google Scholar 

  170. Shen, Y. J., Shen, Y. C., Lee, W. S. & Yang, K. T. Methyl palmitate protects heart against ischemia/reperfusion-induced injury through G-protein coupled receptor 40-mediated activation of the PI3K/AKT pathway. Eur. J. Pharmacol. 905, 174183 (2021).

    Article  CAS  PubMed  Google Scholar 

  171. Hirasawa, A. et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 11, 90–94 (2005).

    Article  CAS  PubMed  Google Scholar 

  172. Murphy, K. A. et al. Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload. Cardiovasc. Res. 118, 1061–1073 (2021).

  173. Witkowski, M., Weeks, T. L. & Hazen, S. L. Gut microbiota and cardiovascular disease. Circ. Res. 127, 553–570 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Tang, T. W. H. et al. Loss of gut microbiota alters immune system composition and cripples postinfarction cardiac repair. Circulation 139, 647–659 (2019).

    Article  CAS  PubMed  Google Scholar 

  175. Pluznick, J. L. et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc. Natl Acad. Sci. USA 110, 4410–4415 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Nemet, I. et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell 180, 862–877 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Romano, K. A. et al. Gut microbiota-generated phenylacetylglutamine and heart failure. Circ. Heart Fail. 16, e009972 (2023).

    Article  CAS  PubMed  Google Scholar 

  178. Pu, J. et al. Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury. Eur. Heart J. 34, 1834–1845 (2013).

    Article  CAS  PubMed  Google Scholar 

  179. Wang, J., Xu, T. & Xu, M. Roles and mechanisms of TGR5 in the modulation of CD4+ T cell functions in myocardial infarction. J. Cardiovasc. Transl. Res. 15, 350–359 (2022).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Z.A. is supported by NIH HL152446.

Author information

Authors and Affiliations

  1. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Emily Flam & Zolt Arany

Authors
  1. Emily Flam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zolt Arany
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.F. and Z.A. wrote the manuscript.

Corresponding author

Correspondence to Zolt Arany.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Cardiovascular Research thanks Yibin Wang, Rong Tian and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Flam, E., Arany, Z. Metabolite signaling in the heart. Nat Cardiovasc Res 2, 504–516 (2023). https://doi.org/10.1038/s44161-023-00270-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44161-023-00270-6

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