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.

CEST MRI reveals a correlation between visceral fat mass and reduced myocardial creatine in obese individuals despite preserved ventricular structure and function

“…[3][4][5] The creatine kinase (CK) system plays an essential role within cardiomyocytes in regulating energy metabolism via the controlled transfer, buffering, and utilization of high energy phosphates from adenosine triphosphate (ATP). 6 Previous studies have consistently shown reduced CK system metabolites including ATP, phospho-creatine (PCr), and creatine across several pathologies of heart failure, [6][7][8][9][10][11] primarily via measurement of either reduced PCr-to-ATP ratio or rate of ATP synthesis through CK flux using 31 P MRS. Reductions in PCr-to-ATP ratio have been demonstrated in patients with ischemic heart disease, 12,13 heart failure with reduced 14,15 or preserved ejection fraction, 16 and hypertrophic cardiomyopathy.…”

Structural correlates of the creatine transporter function regulation: the undiscovered country

“…The potential for therapeutic creatine augmentation in the setting of cardiac myopathies was demonstrated in mouse model of myocardial infraction (Lygate et al 2012) and it has recently been reviewed elsewhere (Zervou et al 2015). Cr supplementation has been reported to have a protective effect in neurons, myoblasts, and cardiomyocytes in culture when the cells are subjected to hypoxic and increased oxidative stressors (Adcock et al 1999(Adcock et al , 2002Balestrino et al 2002;Caretti et al 2010;Santacruz et al 2015a;Sartini et al 2012).…”

Galanin receptors activation modulates myocardial metabolic and antioxidant responses to ischaemia/reperfusion stress

“…might be related to a damage to the sarcolemma. 10 The creatine phosphorylation index expressed as myocardial PCr/Cr ratio was reduced about 2.5 times compared with baseline (0.21 ± 0.03 and 0.51 ± 0.04, respectively, Table S3).…”

“…3 The N-terminal part is a fragment of galanin (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) and the C-terminal part is the other bioactive dipeptide L-carnosine capable of scavenging hydroxyl radicals (Table 1). 6 A fragment of galanin (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) contains residues Trp, 2 Asn, 5 Gly 8 and Tyr, 9 which are necessary for interaction of the peptide with the GalR2 receptor 7,8 and thereby to trigger cardioprotective effects. L-carnosine tailing to C-terminal part of peptide G1 enhances its resistance to the action of exopeptidases due to the insertion of βAla14.…”

“…Post-ischaemic administration of the peptides improved functional recovery of isolated perfused rat hearts and reduced infarct size in rats in vivo. 4,5 The chimeric ligand [βAla14, His15]-galanin (2-15) (G1), which is composed of galanin (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) and the dipeptide carnosine, exhibited the most beneficial effect. 3 The mechanisms of action of peptide G1 remain unclear.…”