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Metabolic Regulation of Human Pluripotent Stem Cell-Derived Cardiomyocyte Maturation

  • Regenerative Medicine (SM Wu, Section Editor)
  • Published:
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Abstract

Purpose of Review

This review summarizes the important role that metabolism plays in driving maturation of human pluripotent stem cell-derived cardiomyocytes.

Recent Findings

Human pluripotent stem cell-derived cardiomyocytes provide a model system for human cardiac biology. However, these models have been unable to fully recapitulate the maturity observed in the adult heart. By simulating the glucose to fatty acid transition observed in neonatal mammals, human pluripotent stem cell-derived cardiomyocytes undergo structural and functional maturation also accompanied by transcriptional changes and cell cycle arrest. The role of metabolism in energy production, signaling, and epigenetic modifications illustrates that metabolism and cellular phenotype are intimately linked.

Summary

Further understanding of key metabolic factors driving cardiac maturation will facilitate the generation of more mature human pluripotent stem cell-derived cardiomyocyte models. This will increase our understanding of cardiac biology and potentially lead to novel therapeutics to enhance heart function.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Inamdar AA, Inamdar AC. Heart Failure: Diagnosis, Management and Utilization. J Clin Med. 2016;5(7).

  2. Writing Group M, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38–360.

    Google Scholar 

  3. Kummitha CM, Kalhan SC, Saidel GM, Lai N. Relating tissue/organ energy expenditure to metabolic fluxes in mouse and human: experimental data integrated with mathematical modeling. Physiol Rep. 2014;2(9).

  4. Mercola M, Colas A, Willems E. Induced pluripotent stem cells in cardiovascular drug discovery. Circ Res. 2013;112(3):534–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Sharma A, Wu JC, Wu SM. Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening. Stem Cell Res Ther. 2013;4(6):150.

    PubMed  PubMed Central  Google Scholar 

  6. Chong JJ, Yang X, Don CW, Minami E, Liu YW, Weyers JJ, et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature. 2014;510(7504):273–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Tabei R, Kawaguchi S, Kanazawa H, Tohyama S, Hirano A, Handa N, et al. Development of a transplant injection device for optimal distribution and retention of human induced pluripotent stem cellderived cardiomyocytes. J Heart Lung Transplant. 2019;38(2):203–14.

  8. Romagnuolo R, Masoudpour H, Porta-Sanchez A, Qiang B, Barry J, Laskary A, et al. Human embryonic stem cell-derived cardiomyocytes regenerate the infarcted pig heart but induce ventricular tachyarrhythmias. Stem Cell Reports. 2019;12(5):967–81.

    PubMed  PubMed Central  Google Scholar 

  9. Weinberger F, Breckwoldt K, Pecha S, Kelly A, Geertz B, Starbatty J, et al. Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells. Sci Transl Med. 2016;8(363):363–148.

    Google Scholar 

  10. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.

    CAS  PubMed  Google Scholar 

  11. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

  12. Protze SI, Lee JH, Keller GM. Human pluripotent stem cell-derived cardiovascular cells: from developmental biology to therapeutic applications. Cell Stem Cell. 2019;25(3):311–27.

    CAS  PubMed  Google Scholar 

  13. Hudson J, Titmarsh D, Hidalgo A, Wolvetang E, Cooper-White J. Primitive cardiac cells from human embryonic stem cells. Stem Cells Dev. 2012;21(9):1513–23.

    CAS  PubMed  Google Scholar 

  14. Tiburcy M, Zimmermann WH. Modeling myocardial growth and hypertrophy in engineered heart muscle. Trends Cardiovasc Med. 2014;24(1):7–13.

    CAS  PubMed  Google Scholar 

  15. Schaaf S, Shibamiya A, Mewe M, Eder A, Stohr A, Hirt MN, et al. Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology. PLoS One. 2011;6(10):e26397.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Voges HK, Mills RJ, Elliott DA, Parton RG, Porrello ER, Hudson JE. Development of a human cardiac organoid injury model reveals innate regenerative potential. Development. 2017;144(6):1118–27.

    CAS  PubMed  Google Scholar 

  17. Tiburcy M, Hudson JE, Balfanz P, Schlick S, Meyer T, Chang Liao ML, et al. Defined engineered human myocardium with advanced maturation for applications in heart failure modeling and repair. Circulation. 2017;135(19):1832–47.

  18. Nunes SS, Miklas JW, Liu J, Aschar-Sobbi R, Xiao Y, Zhang B, et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat Methods. 2013;10(8):781–7.

  19. Shadrin IY, Allen BW, Qian Y, Jackman CP, Carlson AL, Juhas ME, et al. Cardiopatch platform enables maturation and scale-up of human pluripotent stem cell-derived engineered heart tissues. Nat Commun. 2017;8(1):1825.

  20. Zhao Y, Rafatian N, Feric NT, Cox BJ, Aschar-Sobbi R, Wang EY, et al. A platform for generation of chamber-specific cardiac tissues and disease modeling. Cell. 2019;176(4):913–27 e18.

  21. Mills RJ, Hudson JE. Bioengineering adult human heart tissue: how close are we? APL Bioeng. 2019;3(1):010901.

    PubMed  PubMed Central  Google Scholar 

  22. Lemoine MD, Krause T, Koivumaki JT, Prondzynski M, Schulze ML, Girdauskas E, et al. Human induced pluripotent stem cell-derived engineered heart tissue as a sensitive test system for QT prolongation and arrhythmic triggers. Circ Arrhythm Electrophysiol. 2018;11(7):e006035.

    PubMed  Google Scholar 

  23. Andres-Delgado L, Mercader N. Interplay between cardiac function and heart development. Biochim Biophys Acta. 2016;1863(7 Pt B):1707–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Piquereau J, Novotova M, Fortin D, Garnier A, Ventura-Clapier R, Veksler V, et al. Postnatal development of mouse heart: formation of energetic microdomains. J Physiol. 2010;588(Pt 13):2443–54.

  25. Moss AJ. Blood pressure in infants children and adolescents. West J Med. 1981;134(4):296–314.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Porrello ER, Olson EN. A neonatal blueprint for cardiac regeneration. Stem Cell Res. 2014;13(3 Pt B):556–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. •• Quaife-Ryan GA, Sim CB, Ziemann M, Kaspi A, Rafehi H, Ramialison M, et al. Multicellular transcriptional analysis of mammalian heart regeneration. Circulation. 2017;136(12):1123–39 The first transcriptomic framework of multiple cardiac cell populations during cardiac development, repair, and regeneration in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. •• Mills RJ, Titmarsh DM, Koenig X, Parker BL, Ryall JG, Quaife-Ryan GA, et al. Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc Natl Acad Sci U S A. 2017;114(40):E8372-E81 The first study show that simulation of the glycolysis-FAO metabolic transition in hPSC-CMs resulted in advanced cardiac maturation.

    Google Scholar 

  29. •• Nakano H, Minami I, Braas D, Pappoe H, Wu X, Sagadevan A, et al. Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis. Elife. 2017;6 This paper outlined the importance of glucose in cardiac maturation and how very high glucose (indicative of hyperglycemia) results in impaired cardiac maturation through upregulation of nucleotide biosynthesis.

  30. Hidalgo A, Glass N, Ovchinnikov D, Yang SK, Zhang X, Mazzone S, et al. Modelling ischemia-reperfusion injury (IRI) in vitro using metabolically matured induced pluripotent stem cell-derived cardiomyocytes. APL Bioeng. 2018;2(2):026102.

  31. Ramachandra CJA, Mehta A, Wong P, Ja K, Fritsche-Danielson R, Bhat RV, et al. Fatty acid metabolism driven mitochondrial bioenergetics promotes advanced developmental phenotypes in human induced pluripotent stem cell derived cardiomyocytes. Int J Cardiol. 2018;272:288–97.

    PubMed  Google Scholar 

  32. Yang X, Rodriguez ML, Leonard A, Sun L, Fischer KA, Wang Y, et al. Fatty acids enhance the maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cell Reports. 2019;13(4):657–68.

  33. Kamakura T, Makiyama T, Sasaki K, Yoshida Y, Wuriyanghai Y, Chen J, et al. Ultrastructural maturation of human-induced pluripotent stem cell-derived cardiomyocytes in a long-term culture. Circ J. 2013;77(5):1307–14.

  34. Kuppusamy KT, Jones DC, Sperber H, Madan A, Fischer KA, Rodriguez ML, et al. Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes. Proc Natl Acad Sci U S A. 2015;112(21):E2785–94.

  35. Bedada FB, Chan SS, Metzger SK, Zhang L, Zhang J, Garry DJ, et al. Acquisition of a quantitative, stoichiometrically conserved ratiometric marker of maturation status in stem cell-derived cardiac myocytes. Stem Cell Reports. 2014;3(4):594–605.

  36. Mills RJ, Parker BL, Monnot P, Needham EJ, Vivien CJ, Ferguson C, et al. Development of a human skeletal micro muscle platform with pacing capabilities. Biomaterials. 2019;198:217–27.

    CAS  PubMed  Google Scholar 

  37. Schiaffino S, Rossi AC, Smerdu V, Leinwand LA, Reggiani C. Developmental myosins: expression patterns and functional significance. Skelet Muscle. 2015;5:22.

    PubMed  PubMed Central  Google Scholar 

  38. Lundy SD, Zhu WZ, Regnier M, Laflamme MA. Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cells Dev. 2013;22(14):1991–2002.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Hwang HS, Kryshtal DO, Feaster TK, Sanchez-Freire V, Zhang J, Kamp TJ, et al. Comparable calcium handling of human iPSC-derived cardiomyocytes generated by multiple laboratories. J Mol Cell Cardiol. 2015;85:79–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Radisic M, Park H, Shing H, Consi T, Schoen FJ, Langer R, et al. Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds. Proc Natl Acad Sci U S A. 2004;101(52):18129–34.

  41. Parikh SS, Blackwell DJ, Gomez-Hurtado N, Frisk M, Wang L, Kim K, et al. Thyroid and glucocorticoid hormones promote functional T-tubule development in human-induced pluripotent stem cell-derived cardiomyocytes. Circ Res. 2017;121(12):1323–30.

  42. Brette F, Orchard C. T-tubule function in mammalian cardiac myocytes. Circ Res. 2003;92(11):1182–92.

    CAS  PubMed  Google Scholar 

  43. Veerman CC, Mengarelli I, Lodder EM, Kosmidis G, Bellin M, Zhang M, et al. Switch from fetal to adult SCN5A isoform in human induced pluripotent stem cell-derived cardiomyocytes unmasks the cellular phenotype of a conduction disease-causing mutation. J Am Heart Assoc. 2017;6(7).

  44. Quaife-Ryan GA, Sim CB, Porrello ER, Hudson JE. Resetting the epigenome for heart regeneration. Semin Cell Dev Biol. 2016;58:2–13.

    CAS  PubMed  Google Scholar 

  45. Piquereau J, Ventura-Clapier R. Maturation of cardiac energy metabolism during perinatal development. Front Physiol. 2018;9:959.

    PubMed  PubMed Central  Google Scholar 

  46. Birket MJ, Casini S, Kosmidis G, Elliott DA, Gerencser AA, Baartscheer A, et al. PGC-1alpha and reactive oxygen species regulate human embryonic stem cell-derived cardiomyocyte function. Stem Cell Reports. 2013;1(6):560–74.

  47. •• Mills RJ, Parker BL, Quaife-Ryan GA, Voges HK, Needham EJ, Bornot A, et al. Drug screening in human PSC-cardiac organoids identifies pro-proliferative compounds acting via the mevalonate pathway. Cell Stem Cell. 2019; The first study to observe the vital role the mevalonate pathway plays in CM proliferation and how it must be activated to induce regeneration in mature CMs.

  48. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta. 1994;1213(3):263–76.

    CAS  PubMed  Google Scholar 

  49. Piquereau J, Caffin F, Novotova M, Lemaire C, Veksler V, Garnier A, et al. Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell? Front Physiol. 2013;4:102.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Karwi QG, Uddin GM, Ho KL, Lopaschuk GD. Loss of metabolic flexibility in the failing heart. Front Cardiovasc Med. 2018;5:68.

    PubMed  PubMed Central  Google Scholar 

  51. Ronaldson-Bouchard K, Ma SP, Yeager K, Chen T, Song L, Sirabella D, et al. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature. 2018;556(7700):239–43.

  52. Liau B, Zhang D, Bursac N. Functional cardiac tissue engineering. Regen Med. 2012;7(2):187–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Salameh A, Haunschild J, Brauchle P, Peim O, Seidel T, Reitmann M, et al. On the role of the gap junction protein Cx43 (GJA1) in human cardiac malformations with Fallot-pathology. a study on paediatric cardiac specimen. PLoS One. 2014;9(4):e95344.

  54. Vreeker A, van Stuijvenberg L, Hund TJ, Mohler PJ, Nikkels PG, van Veen TA. Assembly of the cardiac intercalated disk during pre- and postnatal development of the human heart. PLoS One. 2014;9(4):e94722.

    PubMed  PubMed Central  Google Scholar 

  55. Herron TJ, Rocha AM, Campbell KF, Ponce-Balbuena D, Willis BC, Guerrero-Serna G, et al. Extracellular matrix-mediated maturation of human pluripotent stem cell-derived cardiac monolayer structure and electrophysiological function. Circ Arrhythm Electrophysiol. 2016;9(4):e003638.

  56. Taegtmeyer H, Young ME, Lopaschuk GD, Abel ED, Brunengraber H, Darley-Usmar V, et al. Assessing cardiac metabolism: a scientific statement from the American Heart Association. Circ Res. 2016;118(10):1659–701.

  57. Lopaschuk GD, Spafford MA, Marsh DR. Glycolysis is predominant source of myocardial ATP production immediately after birth. Am J Phys. 1991;261(6 Pt 2):H1698–705.

    CAS  Google Scholar 

  58. Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016;41(3):211–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Makinde AO, Kantor PF, Lopaschuk GD. Maturation of fatty acid and carbohydrate metabolism in the newborn heart. Mol Cell Biochem. 1998;188(1–2):49–56.

    CAS  PubMed  Google Scholar 

  60. Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013;14:128.

  61. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44(W1):W90–7.

  62. Li T, Zhang Z, Kolwicz SC Jr, Abell L, Roe ND, Kim M, et al. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury. Cell Metab. 2017;25(2):374–85.

  63. Talman V, Teppo J, Poho P, Movahedi P, Vaikkinen A, Karhu ST, et al. Molecular atlas of postnatal mouse heart development. J Am Heart Assoc. 2018;7(20):e010378.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Karwi QG, Jorg AR, Lopaschuk GD. Allosteric, transcriptional and post-translational control of mitochondrial energy metabolism. Biochem J. 2019;476(12):1695–712.

    CAS  PubMed  Google Scholar 

  65. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008;283(16):10892–903.

  66. Hu D, Linders A, Yamak A, Correia C, Kijlstra JD, Garakani A, et al. Metabolic maturation of human pluripotent stem cell-derived cardiomyocytes by inhibition of HIF1alpha and LDHA. Circ Res. 2018;123(9):1066–79.

  67. Gordon EE, Reinking BE, Hu S, Yao J, Kua KL, Younes AK, et al. Maternal hyperglycemia directly and rapidly induces cardiac septal overgrowth in fetal rats. J Diabetes Res. 2015;2015:479565.

    PubMed  PubMed Central  Google Scholar 

  68. •• Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, et al. Hypoxia induces heart regeneration in adult mice. Nature. 2017;541(7636):222–7 This paper demonstrated the necessity of glycolysis for CM proliferation by exposing adult mice to a hypoxic environment, similar to the fetal environment, which re-activated glycolysis and cell cycle.

    CAS  PubMed  Google Scholar 

  69. • Hirose K, Payumo AY, Cutie S, Hoang A, Zhang H, Guyot R, et al. Evidence for hormonal control of heart regenerative capacity during endothermy acquisition. Science. 2019;364(6436):184–8 This study outlined the role of T3 regulation of endothermy which increases the metabolic rate and is responsible for the changes in regenerative capacity in 41 species.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Correia C, Koshkin A, Duarte P, Hu D, Teixeira A, Domian I, et al. Distinct carbon sources affect structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Sci Rep. 2017;7(1):8590.

  71. Ulmer BM, Stoehr A, Schulze ML, Patel S, Gucek M, Mannhardt I, et al. Contractile work contributes to maturation of energy metabolism in hiPSC-derived cardiomyocytes. Stem Cell Reports. 2018;10(3):834–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Yang X, Rodriguez M, Pabon L, Fischer KA, Reinecke H, Regnier M, et al. Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. J Mol Cell Cardiol. 2014;72:296–304.

  73. Hirt MN, Boeddinghaus J, Mitchell A, Schaaf S, Bornchen C, Muller C, et al. Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation. J Mol Cell Cardiol. 2014;74:151–61.

    CAS  PubMed  Google Scholar 

  74. Lemme M, Braren I, Prondzynski M, Aksehirlioglu B, Ulmer BM, Schulze ML, et al. Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue. Cardiovasc Res. 2019.

  75. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1(7285):785–9.

    CAS  PubMed  Google Scholar 

  76. Fillmore N, Levasseur JL, Fukushima A, Wagg CS, Wang W, Dyck JRB, et al. Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure with preserved ejection fraction. Mol Med. 2018;24(1):3.

  77. Li F, Wang X, Capasso JM, Gerdes AM. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol. 1996;28(8):1737–46.

    CAS  PubMed  Google Scholar 

  78. Broughton KM, Wang BJ, Firouzi F, Khalafalla F, Dimmeler S, Fernandez-Aviles F, et al. Mechanisms of cardiac repair and regeneration. Circ Res. 2018;122(8):1151–63.

  79. Mohamed TMA, Ang YS, Radzinsky E, Zhou P, Huang Y, Elfenbein A, et al. Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell. 2018;173(1):104–16 e12.

  80. Leach JP, Heallen T, Zhang M, Rahmani M, Morikawa Y, Hill MC, et al. Hippo pathway deficiency reverses systolic heart failure after infarction. Nature. 2017;550(7675):260–4.

  81. Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell. 2014;157(3):565–79.

  82. Liu Q, Lopez K, Murnane J, Humphrey T, Barcellos-Hoff MH. Misrepair in context: TGFbeta regulation of DNA repair. Front Oncol. 2019;9:799.

    PubMed  PubMed Central  Google Scholar 

  83. Yoon MJ, Lee GY, Chung JJ, Ahn YH, Hong SH, Kim JB. Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes. 2006;55(9):2562–70.

    CAS  PubMed  Google Scholar 

  84. Wang W, Xiao ZD, Li X, Aziz KE, Gan B, Johnson RL, et al. AMPK modulates hippo pathway activity to regulate energy homeostasis. Nat Cell Biol. 2015;17(4):490–9.

  85. Engel FB, Schebesta M, Duong MT, Lu G, Ren S, Madwed JB, et al. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev. 2005;19(10):1175–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Monroe TO, Hill MC, Morikawa Y, Leach JP, Heallen T, Cao S, et al. YAP partially reprograms chromatin accessibility to directly induce adult cardiogenesis in vivo. Dev Cell. 2019;48(6):765–79 e7.

    PubMed  PubMed Central  Google Scholar 

  87. Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem. 2007;40(9–10):575–84.

    CAS  PubMed  Google Scholar 

  88. Hinson DD, Chambliss KL, Toth MJ, Tanaka RD, Gibson KM. Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways. J Lipid Res. 1997;38(11):2216–23.

    CAS  PubMed  Google Scholar 

  89. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996;65:241–69.

    CAS  PubMed  Google Scholar 

  90. Cohen LH, Pieterman E, van Leeuwen RE, Overhand M, Burm BE, van der Marel GA, et al. Inhibitors of prenylation of Ras and other G-proteins and their application as therapeutics. Biochem Pharmacol. 2000;60(8):1061–8.

    CAS  PubMed  Google Scholar 

  91. Calero M, Chen CZ, Zhu W, Winand N, Havas KA, Gilbert PM, et al. Dual prenylation is required for Rab protein localization and function. Mol Biol Cell. 2003;14(5):1852–67.

  92. Molnar G, Dagher MC, Geiszt M, Settleman J, Ligeti E. Role of prenylation in the interaction of rho-family small GTPases with GTPase activating proteins. Biochemistry. 2001;40(35):10542–9.

    CAS  PubMed  Google Scholar 

  93. Prieto-Dominguez N, Parnell C, Teng Y. Drugging the small GTPase pathways in cancer treatment: promises and challenges. Cells. 2019;8(3).

  94. Berndt N, Hamilton AD, Sebti SM. Targeting protein prenylation for cancer therapy. Nat Rev Cancer. 2011;11(11):775–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Muhlhauser U, Zolk O, Rau T, Munzel F, Wieland T, Eschenhagen T. Atorvastatin desensitizes beta-adrenergic signaling in cardiac myocytes via reduced isoprenylation of G-protein gamma-subunits. FASEB J. 2006;20(6):785–7.

    PubMed  Google Scholar 

  96. Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation. J Nutr. 2006;136(1 Suppl):207S–11S.

    CAS  PubMed  Google Scholar 

  97. Harper AE, Miller RH, Block KP. Branched-chain amino acid metabolism. Annu Rev Nutr. 1984;4:409–54.

    CAS  PubMed  Google Scholar 

  98. Uddin GM, Zhang L, Shah S, Fukushima A, Wagg CS, Gopal K, et al. Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure. Cardiovasc Diabetol. 2019;18(1):86.

  99. • Shao D, Villet O, Zhang Z, Choi SW, Yan J, Ritterhoff J, et al. Glucose promotes cell growth by suppressing branched-chain amino acid degradation. Nat Commun. 2018;9(1):2935. This paper outlined that high glucose is required to inhibit BCAA degradation and the subsequent accumulation of BCAAs activates mTOR signaling which is involved in CM hypertrophy.

  100. Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev. 1980;60(1):143–87.

    CAS  PubMed  Google Scholar 

  101. Pinckaers PJ, Churchward-Venne TA, Bailey D, van Loon LJ. Ketone bodies and exercise performance: the next magic bullet or merely hype? Sports Med. 2017;47(3):383–91.

    PubMed  Google Scholar 

  102. McGarry JD, Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem. 1980;49:395–420.

    CAS  PubMed  Google Scholar 

  103. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15(6):412–26.

    CAS  PubMed  Google Scholar 

  104. Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133(8):698–705.

  105. Horton JL, Davidson MT, Kurishima C, Vega RB, Powers JC, Matsuura TR, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight. 2019;4(4).

  106. Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation. 1996;94(11):2837–42.

    CAS  PubMed  Google Scholar 

  107. Christe ME, Rodgers RL. Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat. J Mol Cell Cardiol. 1994;26(10):1371–5.

    CAS  PubMed  Google Scholar 

  108. Vitaterna MH, Takahashi JS, Turek FW. Overview of circadian rhythms. Alcohol Res Health. 2001;25(2):85–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Fan L, Hsieh PN, Sweet DR, Jain MK. Kruppel-like factor 15: regulator of BCAA metabolism and circadian protein rhythmicity. Pharmacol Res. 2018;130:123–6.

    CAS  PubMed  Google Scholar 

  110. Prosdocimo DA, John JE, Zhang L, Efraim ES, Zhang R, Liao X, et al. KLF15 and PPARalpha cooperate to regulate cardiomyocyte lipid gene expression and oxidation. PPAR Res. 2015;2015:201625.

  111. Jeyaraj D, Scheer FA, Ripperger JA, Haldar SM, Lu Y, Prosdocimo DA, et al. Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab. 2012;15(3):311–23.

  112. Gray S, Wang B, Orihuela Y, Hong EG, Fisch S, Haldar S, et al. Regulation of gluconeogenesis by Kruppel-like factor 15. Cell Metab. 2007;5(4):305–12.

  113. Haldar SM, Lu Y, Jeyaraj D, Kawanami D, Cui Y, Eapen SJ, et al. Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation. Sci Transl Med. 2010;2(26):26ra.

    Google Scholar 

  114. Fisch S, Gray S, Heymans S, Haldar SM, Wang B, Pfister O, et al. Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A. 2007;104(17):7074–9.

  115. Zhang L, Prosdocimo DA, Bai X, Fu C, Zhang R, Campbell F, et al. KLF15 establishes the landscape of diurnal expression in the heart. Cell Rep. 2015;13(11):2368–75.

  116. • Noack C, Iyer LM, Liaw NY, Schoger E, Khadjeh S, Wagner E, et al. KLF15-Wnt-dependent cardiac reprogramming up-regulates SHISA3 in the mammalian heart. J Am Coll Cardiol. 2019;74(14):1804–19. This paper further illustrated the significance of KLF15's role in regulation of metabolism whilst also demonstrating its importance for contractility and in preventing pathological remodeling.

  117. Dierickx P, Vermunt MW, Muraro MJ, Creyghton MP, Doevendans PA, van Oudenaarden A, et al. Circadian networks in human embryonic stem cell-derived cardiomyocytes. EMBO Rep. 2017;18(7):1199–212.

  118. Zhang Z, Tan M, Xie Z, Dai L, Chen Y, Zhao Y. Identification of lysine succinylation as a new post-translational modification. Nat Chem Biol. 2011;7(1):58–63.

    CAS  PubMed  Google Scholar 

  119. He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429(6988):188–93.

    CAS  PubMed  Google Scholar 

  120. Fukushima A, Alrob OA, Zhang L, Wagg CS, Altamimi T, Rawat S, et al. Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart. Am J Physiol Heart Circ Physiol. 2016;311(2):H347–63.

  121. Ritterhoff J, Tian R. Metabolism in cardiomyopathy: every substrate matters. Cardiovasc Res. 2017;113(4):411–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Aguiar CJ, Rocha-Franco JA, Sousa PA, Santos AK, Ladeira M, Rocha-Resende C, et al. Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation. Cell Commun Signal. 2014;12:78.

    PubMed  PubMed Central  Google Scholar 

  123. Alexander D, Lombardi R, Rodriguez G, Mitchell MM, Marian AJ. Metabolomic distinction and insights into the pathogenesis of human primary dilated cardiomyopathy. Eur J Clin Investig. 2011;41(5):527–38.

    Google Scholar 

  124. Mueller-Hennessen M, Sigl J, Fuhrmann JC, Witt H, Reszka R, Schmitz O, et al. Metabolic profiles in heart failure due to non-ischemic cardiomyopathy at rest and under exercise. ESC Heart Fail. 2017;4(2):178–89.

  125. Lucas DT, Szweda LI. Declines in mitochondrial respiration during cardiac reperfusion: age-dependent inactivation of alpha-ketoglutarate dehydrogenase. Proc Natl Acad Sci U S A. 1999;96(12):6689–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Tretter L, Adam-Vizi V. Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond Ser B Biol Sci. 2005;360(1464):2335–45.

    CAS  Google Scholar 

  127. Omede A, Zi M, Prehar S, Maqsood A, Stafford N, Mamas M, et al. The oxoglutarate receptor 1 (OXGR1) modulates pressure overload-induced cardiac hypertrophy in mice. Biochem Biophys Res Commun. 2016;479(4):708–14.

  128. Cai X, Zhu C, Xu Y, Jing Y, Yuan Y, Wang L, et al. Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways. Sci Rep. 2016;6:26802.

  129. Yao K, Yin Y, Li X, Xi P, Wang J, Lei J, et al. Alpha-ketoglutarate inhibits glutamine degradation and enhances protein synthesis in intestinal porcine epithelial cells. Amino Acids. 2012;42(6):2491–500.

  130. Burnstock G. Purinergic nerves. Pharmacol Rev. 1972;24(3):509–81.

    CAS  Google Scholar 

  131. Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev. 1998;50(3):413–92.

    CAS  PubMed  Google Scholar 

  132. Drury AN, Szent-Gyorgyi A. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol. 1929;68(3):213–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Delacretaz E. Clinical practice. Supraventricular tachycardia. N Engl J Med. 2006;354(10):1039–51.

    CAS  PubMed  Google Scholar 

  134. Liang X, Samways DSK, Cox J, Egan TM. Ca(2+) flux through splice variants of the ATP-gated ionotropic receptor P2X7 is regulated by its cytoplasmic N terminus. J Biol Chem. 2019;294(33):12521–33.

    CAS  PubMed  Google Scholar 

  135. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet. 1999;23(2):147.

    CAS  PubMed  Google Scholar 

  136. Momiyama Y, Furutani M, Suzuki Y, Ohmori R, Imamura S, Mokubo A, et al. A mitochondrial DNA variant associated with left ventricular hypertrophy in diabetes. Biochem Biophys Res Commun. 2003;312(3):858–64.

  137. Jia Z, Zhang Y, Li Q, Ye Z, Liu Y, Fu C, et al. A coronary artery disease-associated tRNAThr mutation altered mitochondrial function, apoptosis and angiogenesis. Nucleic Acids Res. 2019;47(4):2056–74.

  138. Selhub J. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging. 2002;6(1):39–42.

    CAS  PubMed  Google Scholar 

  139. Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017;25(1):27–42.

    CAS  PubMed  Google Scholar 

  140. Lu SC. S-Adenosylmethionine. Int J Biochem Cell Biol. 2000;32(4):391–5.

    CAS  PubMed  Google Scholar 

  141. Sperber H, Mathieu J, Wang Y, Ferreccio A, Hesson J, Xu Z, et al. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol. 2015;17(12):1523–35.

  142. Xu Z, Robitaille AM, Berndt JD, Davidson KC, Fischer KA, Mathieu J, et al. Wnt/beta-catenin signaling promotes self-renewal and inhibits the primed state transition in naive human embryonic stem cells. Proc Natl Acad Sci U S A. 2016;113(42):E6382–E90.

  143. Keating ST, El-Osta A. Epigenetics and metabolism. Circ Res. 2015;116(4):715–36.

    CAS  PubMed  Google Scholar 

  144. Mews P, Donahue G, Drake AM, Luczak V, Abel T, Berger SL. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature. 2017;546(7658):381–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Roth SY, Denu JM, Allis CD. Histone acetyltransferases. Annu Rev Biochem. 2001;70:81–120.

    CAS  PubMed  Google Scholar 

  146. Cai L, Sutter BM, Li B, Tu BP. Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol Cell. 2011;42(4):426–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Takahashi H, McCaffery JM, Irizarry RA, Boeke JD. Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol Cell. 2006;23(2):207–17.

    CAS  PubMed  Google Scholar 

  148. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009;324(5930):1076–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Sim CB, Ziemann M, Kaspi A, Harikrishnan KN, Ooi J, Khurana I, et al. Dynamic changes in the cardiac methylome during postnatal development. FASEB J. 2015;29(4):1329–43.

  150. Gilsbach R, Schwaderer M, Preissl S, Gruning BA, Kranzhofer D, Schneider P, et al. Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo. Nat Commun. 2018;9(1):391.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

J.E.H. was supported by Fellowships from the National Health and Medical Research Council of Australia, the National Heart Foundation of Australia, and the QIMR Berghofer Medical Research Institute.

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  1. QIMR Berghofer Medical Research Institute, 300 Herston Rd, Brisbane, Queensland, 4006, Australia

    Christopher A. P. Batho, Richard J. Mills & James E. Hudson

  2. School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia

    Christopher A. P. Batho

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Correspondence to James E. Hudson.

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Conflict of Interest

Christopher A.P. Batho declares that he has no conflict of interest.

Richard J. Mills is a co-founder of Dynomics Inc., a heart failure therapeutics company. He is also listed as a co-inventor on pending patents held by The University of Queensland and QIMR Berghofer Medical Research Institute that relate to cardiac organoid maturation and putative cardiac regeneration therapeutics.

James E. Hudson reports non-financial support from AstraZeneca, and he is a founding member of Dynomics Inc., a heart failure therapeutics company. He is also named on multiple patents for differentiation, maturation, tissue engineering protocols, and targets for regenerative therapeutics (some licensed to companies Myriamed & Repairon).

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All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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Batho, C.A.P., Mills, R.J. & Hudson, J.E. Metabolic Regulation of Human Pluripotent Stem Cell-Derived Cardiomyocyte Maturation. Curr Cardiol Rep 22, 73 (2020). https://doi.org/10.1007/s11886-020-01303-3

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