Background: Multiple studies suggest creatine mediates anti-oxidant activity in addition to its established role in cellular
energy metabolism. The functional significance for the heart has yet to be established, but antioxidant activity could
contribute to the cardioprotective effect of creatine in ischaemia/reperfusion injury.
Objectives: To determine whether intracellular creatine levels influence responses to acute reactive oxygen species (ROS)
exposure in the intact beating heart. We hypothesised that mice with elevated creatine due to over-expression of the
creatine transporter (CrT-OE) would be relatively protected, while mice with creatine-deficiency (GAMT KO) would fare
worse.
Methods and Results: CrT-OE mice were pre-selected for creatine levels 20–100% above wild-type using in vivo 1
H–
MRS.
Hearts were perfused in isovolumic Langendorff mode and cardiac function monitored throughout. After 20 min
equilibration, hearts were perfused with either H2O2 0.5 mM (30 min), or the anti-neoplastic drug doxorubicin 15 mM
(100 min). Protein carbonylation, creatine kinase isoenzyme activities and phospho-PKCd expression were quantified in
perfused hearts as markers of oxidative damage and apoptotic signalling. Wild-type hearts responded to ROS challenge
with a profound decline in contractile function that was ameliorated by co-administration of catalase or dexrazoxane as
positive controls. In contrast, the functional deterioration in CrT-OE and GAMT KO hearts was indistinguishable from wildtype
controls, as was the extent of oxidative damage and apoptosis. Exogenous creatine supplementation also failed to
protect hearts from doxorubicin-induced dysfunction.
Conclusions: Intracellular creatine levels do not influence the response to acute ROS challenge in the intact beating heart,
arguing against creatine exerting (patho-)physiologically relevant anti-oxidant activity