Augmentation of Creatine in the Heart

Abstract

Creatine is a principle component of the creatine kinase (CK) phosphagen system common to all vertebrates. It is found in excitable cells, such as cardiomyocytes, where it plays an important role in the buffering and transport of chemical energy to ensure that supply meets the dynamic demands of the heart. Multiple components of the CK system, including intracellular creatine levels, are reduced in heart failure, while ischaemia and hypoxia represent acute crises of energy provision. Elevation of myocardial creatine levels has therefore been suggested as potentially beneficial, however, achieving this goal is not trivial. This mini-review outlines the evidence in support of creatine elevation and critically examines the pharmacological approaches that are currently available. In particular, dietary creatine-supplementation does not sufficiently elevate creatine levels in the heart due to subsequent down-regulation of the plasma membrane creatine transporter (CrT). Attempts to increase passive diffusion and bypass the CrT, e.g. via creatine esters, have yet to be tested in the heart. However, studies in mice with genetic overexpression of the CrT demonstrate proof-of-principle that elevated creatine protects the heart from ischaemia-reperfusion injury. This suggests activation of the CrT as a major unmet pharmacological target. However, translation of this finding to the clinic will require a greater understanding of CrT regulation in health and disease and the development of small molecule activators.

Fig. (1)

Creatine biosynthesis and the CK energy shuttle: Creatine biosynthesis is a two-step process with L-arginine:glycine amidinotransferase (AGAT), mostly in the kidney, and N-guanidinoacetate methyltransferase (GAMT) predominantly in the liver. Creatine is taken-up into cardiomyocytes from the bloodstream by the plasma-membrane creatine transporter (CrT). Mitochondrial creatine kinase (Mt-CK) located in the mitochondrial inter-membrane space catalyses direct transfer of a high-energy phosphoryl group from ATP to creatine to form phosphocreatine (PCr). PCr is small and less polar than ATP and accumulates to high levels in the cytosol acting as a highly mobile, short-term, energy store. The reverse reaction generates ATP and is catalysed by the cystolic CK dimers closely coupled to ATPases. The liberated creatine diffuses back to signal for further ATP production. Compartmentalisation of the reactants without the requirement for ADP and ATP diffusion ensure metabolites are at favourable levels to support forward and reverse reactions and maximise the free energy available from ATP hydrolysis, i.e. low [ATP/ADP] ratio at the mitochondria and high [ATP/ADP] at the ATPases [1, 2, 4, 5]. Created using Servier Medical Art by Servier which is licensed under a Creative Commons Attribution 3.0 Unported License http://www.servier.com/ slidekit.

Fig. (2)

Structures of precursor GAA, Creatine, b-GPA, creatinine and Cr analogues.

Fig. (3)

³¹P-NMR spectra from ex vivo Langendorff perfused mouse heart. The left panel is from a wild-type mouse showing a large phosphocreatine (PCr) peak and the three phosphoryl groups of ATP. On the right is a spectrum from a creatine transporter over-expressing mouse (Oxford) heart showing greatly increased PCr peak.