Advertisement

The Myocardial Creatine Kinase System in the Normal, Ischaemic and Failing Heart

  • Craig A. LygateEmail author
  • Stefan Neubauer
Chapter
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 11)

Abstract

The creatine kinase (CK) system is the final step in cardiac energy metabolism providing a direct link between energy production in the mitochondria and energy utilising ATPases. It acts as an energy storage and transport mechanism and maintains favourable local ATP/ADP ratios, thereby supporting further energy production and high levels of free energy from ATP hydrolysis. Down-regulation of CK activity and myocardial creatine levels is a universal finding in chronic heart failure, and the degree of impairment has been shown to be an excellent prognostic indicator in patients. However, it is unclear whether these changes represent epiphenomenon or contribute to disease pathophysiology. This chapter focuses on attempts over the past 20 years to address this question using genetic loss-of-function models in the mouse. Findings from these models have been equivocal and at times contradictory, however, recent evidence suggests that loss of creatine or CK is not detrimental in surgical models of chronic heart failure, providing the clearest evidence to date that such changes do not contribute to dysfunction. Despite this conclusion, over-expression of CK in mouse heart has been found to protect against heart failure and improve survival. In the setting of ischaemia-reperfusion injury, loss of creatine or CK impairs functional recovery and augmentation of either is cardioprotective. We are therefore entering an exciting new era of research in this field aimed at understanding the benefits of CK system augmentation and identifying new mechanisms to achieve this without genetic modification for possible future clinical translation.

Keywords

Creatine kinase Phosphagen systems Cardiac energetics Genetically-modified mice Heart failure Ischaemia Reperfusion injury 

Notes

Acknowledgements

Work in the authors’ laboratory is funded by the British Heart Foundation (Programme grant RG/13/8/30266).

References

  1. 1.
    Schlattner U, Tokarska-Schlattner M, Wallimann T (2006) Mitochondrial creatine kinase in human health and disease. Biochim Biophys Acta 1762:164–180PubMedCrossRefGoogle Scholar
  2. 2.
    Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213PubMedGoogle Scholar
  3. 3.
    Ingwall JS, Weiss RG (2004) Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 95:135–145PubMedCrossRefGoogle Scholar
  4. 4.
    Neubauer S (2007) The failing heart–an engine out of fuel. N Engl J Med 356:1140–1151PubMedCrossRefGoogle Scholar
  5. 5.
    Wallimann T, Wyss M, Brdiczka D et al (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 281(Pt 1):21–40PubMedCentralPubMedGoogle Scholar
  6. 6.
    Sylven C, Lin L, Kallner A et al (1991) Dynamics of creatine kinase shuttle enzymes in the human heart. Eur J Clin Invest 21:350–354PubMedCrossRefGoogle Scholar
  7. 7.
    Lygate CA, Fischer A, Sebag-Montefiore L et al (2007) The creatine kinase energy transport system in the failing mouse heart. J Mol Cell Cardiol 42:1129–1136PubMedCrossRefGoogle Scholar
  8. 8.
    Shen W, Asai K, Uechi M et al (1999) Progressive loss of myocardial ATP due to a loss of total purines during the development of heart failure in dogs: a compensatory role for the parallel loss of creatine. Circulation 100:2113–2118PubMedCrossRefGoogle Scholar
  9. 9.
    Neubauer S, Remkes H, Spindler M et al (1999) Downregulation of the Na(+)-creatine cotransporter in failing human myocardium and in experimental heart failure. Circulation 100:1847–1850PubMedCrossRefGoogle Scholar
  10. 10.
    Tian R, Nascimben L, Kaddurah-Daouk R et al (1996) Depletion of energy reserve via the creatine kinase reaction during the evolution of heart failure in cardiomyopathic hamsters. J Mol Cell Cardiol 28:755–765PubMedCrossRefGoogle Scholar
  11. 11.
    Maslov MY, Chacko VP, Stuber M et al (2007) Altered high-energy phosphate metabolism predicts contractile dysfunction and subsequent ventricular remodeling in pressure-overload hypertrophy mice. Am J Physiol Heart Circ Physiol 292:H387–H391PubMedGoogle Scholar
  12. 12.
    Neubauer S, Krahe T, Schindler R et al (1992) 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 86:1810–1818PubMedCrossRefGoogle Scholar
  13. 13.
    Neubauer S, Horn M, Pabst T et al (1995) Contributions of 31P-magnetic resonance spectroscopy to the understanding of dilated heart muscle disease. Eur Heart J 16:115–118PubMedCrossRefGoogle Scholar
  14. 14.
    Neubauer S, Horn M, Cramer M et al (1997) Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96:2190–2196PubMedCrossRefGoogle Scholar
  15. 15.
    Oudman I, Clark JF, Brewster LM (2013) The effect of the creatine analogue beta-guanidinopropionic acid on energy metabolism: a systematic review. PLoS One 8:e52879PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Bloch K, Schoenheimer R, Rittenberg D (1941) Rate of formation and disappearance of body creatine in normal animals. J Biol Chem 138:155–166Google Scholar
  17. 17.
    Wiesner RJ, Hornung TV, Garman JD et al (1999) Stimulation of mitochondrial gene expression and proliferation of mitochondria following impairment of cellular energy transfer by inhibition of the phosphocreatine circuit in rat hearts. J Bioenerg Biomembr 31:559–567PubMedCrossRefGoogle Scholar
  18. 18.
    Mekhfi H, Hoerter J, Lauer C et al (1990) Myocardial adaptation to creatine deficiency in rats fed with beta-guanidinopropionic acid, a creatine analogue. Am J Physiol Heart Circ Physiol 258:H1151–H1158Google Scholar
  19. 19.
    Kapelko VI, Kupriyanov VV, Novikova NA et al (1988) The cardiac contractile failure induced by chronic creatine and phosphocreatine deficiency. J Mol Cell Cardiol 20:465–479PubMedCrossRefGoogle Scholar
  20. 20.
    Hamman BL, Bittl JA, Jacobus WE et al (1995) Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts. Am J Physiol Heart Circ Physiol 269:H1030–H1036Google Scholar
  21. 21.
    Tian R, Ingwall JS (1996) Energetic basis for reduced contractile reserve in isolated rat hearts. Am J Physiol 270:H1207–H1216PubMedGoogle Scholar
  22. 22.
    van Deursen J, Heerschap A, Oerlemans F et al (1993) Skeletal muscles of mice deficient in muscle creatine kinase lack burst activity. Cell 74:621–631PubMedCrossRefGoogle Scholar
  23. 23.
    Steeghs K, Heerschap A, de Haan A et al (1997) Use of gene targeting for compromising energy homeostasis in neuro-muscular tissues: the role of sarcomeric mitochondrial creatine kinase. J Neurosci Methods 71:29–41PubMedCrossRefGoogle Scholar
  24. 24.
    Steeghs K, Benders A, Oerlemans F et al (1997) Altered Ca2+ responses in muscles with combined mitochondrial and cytosolic creatine kinase deficiencies. Cell 89:93–103PubMedCrossRefGoogle Scholar
  25. 25.
    Ventura-Clapier R, Kuznetsov AV, d’Albis A et al (1995) Muscle creatine kinase-deficient mice. I. Alterations in myofibrillar function. J Biol Chem 270:19914–19920PubMedCrossRefGoogle Scholar
  26. 26.
    Van Dorsten FA, Nederhoff MG, Nicolay K et al (1998) 31P NMR studies of creatine kinase flux in M-creatine kinase-deficient mouse heart. Am J Physiol Heart Circ Physiol 275:H1191–H1199Google Scholar
  27. 27.
    Saupe KW, Spindler M, Tian R et al (1998) Impaired cardiac energetics in mice lacking muscle-specific isoenzymes of creatine kinase. Circ Res 82:898–907PubMedCrossRefGoogle Scholar
  28. 28.
    Nahrendorf M, Spindler M, Hu K et al (2005) Creatine kinase knockout mice show left ventricular hypertrophy and dilatation, but unaltered remodeling post-myocardial infarction. Cardiovasc Res 65:419–427PubMedCrossRefGoogle Scholar
  29. 29.
    Lygate CA, Medway DJ, Ostrowski PJ et al (2012) Chronic creatine kinase deficiency eventually leads to congestive heart failure, but severity is dependent on genetic background, gender and age. Basic Res Cardiol 107:276PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Spindler M, Niebler R, Remkes H et al (2002) Mitochondrial creatine kinase is critically necessary for normal myocardial high-energy phosphate metabolism. Am J Physiol Heart Circ Physiol 283:H680–H687PubMedGoogle Scholar
  31. 31.
    Bonz AW, Kniesch S, Hofmann U et al (2002) Functional properties and Ca(2+). (i) metabolism of creatine kinase–KO mice myocardium. Biochem Biophys Res Commun 298:163–168PubMedCrossRefGoogle Scholar
  32. 32.
    Gustafson LA, Van Beek JH (2002) Activation time of myocardial oxidative phosphorylation in creatine kinase and adenylate kinase knockout mice. Am J Physiol Heart Circ Physiol 282:H2259–H2264PubMedGoogle Scholar
  33. 33.
    Spindler M, Meyer K, Stromer H et al (2004) Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis. Am J Physiol Heart Circ Physiol 287:H1039–H1045PubMedGoogle Scholar
  34. 34.
    Saupe KW, Spindler M, Hopkins JC et al (2000) Kinetic, thermodynamic, and developmental consequences of deleting creatine kinase isoenzymes from the heart. Reaction kinetics of the creatine kinase isoenzymes in the intact heart. J Biol Chem 275:19742–19746PubMedCrossRefGoogle Scholar
  35. 35.
    Crozatier B, Badoual T, Boehm E et al (2002) Role of creatine kinase in cardiac excitation-contraction coupling: studies in creatine kinase-deficient mice. FASEB J 16:653–660PubMedCrossRefGoogle Scholar
  36. 36.
    Lygate CA, Hunyor I, Medway D et al (2009) Cardiac phenotype of mitochondrial creatine kinase knockout mice is modified on a pure C57BL/6 genetic background. J Mol Cell Cardiol 46:93–99PubMedCrossRefGoogle Scholar
  37. 37.
    Nahrendorf M, Streif JU, Hiller KH et al (2006) Multimodal functional cardiac MR imaging in creatine kinase deficient mice reveals subtle abnormalities in myocardial perfusion and mechanics. Am J Physiol Heart Circ Physiol 290:H2516–H2521PubMedGoogle Scholar
  38. 38.
    Schmidt A, Marescau B, Boehm EA et al (2004) Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency. Hum Mol Genet 13:905–921PubMedCrossRefGoogle Scholar
  39. 39.
    Kan HE, Renema WK, Isbrandt D et al (2004) Phosphorylated guanidinoacetate partly compensates for the lack of phosphocreatine in skeletal muscle of mice lacking guanidinoacetate methyltransferase. J Physiol 560:219–229PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    ten Hove M, Lygate CA, Fischer A et al (2005) Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice. Circulation 111:2477–2485PubMedCrossRefGoogle Scholar
  41. 41.
    Lygate CA, Aksentijevic D, Dawson D et al (2013) Living without creatine: unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice. Circ Res 112:945–955PubMedCrossRefGoogle Scholar
  42. 42.
    Branovets J, Sepp M, Kotlyarova S et al (2013) Unchanged mitochondrial organization and compartmentation of high-energy phosphates in creatine-deficient GAMT−/− mouse hearts. Am J Physiol Heart Circ Physiol 305:H506–H520PubMedCentralPubMedGoogle Scholar
  43. 43.
    Choe C-u, Nabuurs C, Stockebrand MC et al (2013) l-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome. Hum Mol Genet 22:110–123CrossRefGoogle Scholar
  44. 44.
    Lorentzon M, Ramunddal T, Bollano E et al (2007) In vivo effects of myocardial creatine depletion on left ventricular function, morphology, and energy metabolism–consequences in acute myocardial infarction. J Card Fail 13:230–237PubMedCrossRefGoogle Scholar
  45. 45.
    Horn M, Remkes H, Stromer H et al (2001) Chronic phosphocreatine depletion by the creatine analogue beta-guanidinopropionate is associated with increased mortality and loss of ATP in rats after myocardial infarction. Circulation 104:1844–1849PubMedCrossRefGoogle Scholar
  46. 46.
    Boehm EA, Radda GK, Tomlin H et al (1996) The utilisation of creatine and its analogues by cytosolic and mitochondrial creatine kinase. Biochim Biophys Acta 1274:119–128PubMedCrossRefGoogle Scholar
  47. 47.
    Wallis J, Lygate CA, Fischer A et al (2005) Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure: insights from creatine transporter-overexpressing transgenic mice. Circulation 112:3131–3139PubMedCrossRefGoogle Scholar
  48. 48.
    Phillips D, ten Hove M, Schneider JE et al (2010) Mice over-expressing the myocardial creatine transporter develop progressive heart failure and show decreased glycolytic capacity. J Mol Cell Cardiol 48:582–590PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Lygate CA, Bohl S, ten Hove M et al (2012) Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction. Cardiovasc Res 96:466–475PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Schneider JE, Tyler DJ, ten Hove M et al (2004) In vivo cardiac 1H-MRS in the mouse. Magn Reson Med 52:1029–1035PubMedCrossRefGoogle Scholar
  51. 51.
    Wu F, Zhang J, Beard DA (2009) Experimentally observed phenomena on cardiac energetics in heart failure emerge from simulations of cardiac metabolism. Proc Natl Acad Sci U S A 106:7143–7148PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Gupta A, Akki A, Wang Y et al (2012) Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved. J Clin Invest 122:291–302PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Vanoverschelde JL, Janier MF, Bakke JE et al (1994) Rate of glycolysis during ischemia determines extent of ischemic injury and functional recovery after reperfusion. Am J Physiol Heart Circ Physiol 267:H1785–H1794Google Scholar
  54. 54.
    Akki A, Su J, Yano T et al (2012) Creatine kinase over-expression improves ATP kinetics and contractile function in post-ischemic myocardium. Am J Physiol Heart Circ Physiol 303:H844–H852PubMedCentralPubMedGoogle Scholar
  55. 55.
    Dolder M, Walzel B, Speer O et al (2003) Inhibition of the mitochondrial permeability transition by creatine kinase substrates. Requirement for microcompartmentation. J Biol Chem 278:17760–17766PubMedCrossRefGoogle Scholar
  56. 56.
    Zervou S, Ray T, Sahgal N et al (2013) A role for thioredoxin-interacting protein (Txnip) in cellular creatine homeostasis. Am J Physiol Endocrinol Metab 305:E263–E270PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Division of Cardiovascular Medicine, Radcliffe Department of MedicineUniversity of Oxford, Wellcome Trust Centre for Human GeneticsOxfordUK
  2. 2.Division of Cardiovascular Medicine, Radcliffe Department of MedicineUniversity of OxfordOxfordUK

Personalised recommendations