Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction.
OBJECTIVE
Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury.


RESULTS
CrT-OE mice were selected for left ventricular (LV) creatine 20-100% above wild-type values and subjected to acute and chronic coronary artery ligation. Increasing myocardial creatine up to 100% was not detrimental even in ageing CrT-OE. In chronic heart failure, creatine elevation was neither beneficial nor detrimental, with no effect on survival, LV remodelling or dysfunction. However, CrT-OE hearts were protected against I/R injury in vivo in a dose-dependent manner (average 27% less myocardial necrosis) and exhibited greatly improved functional recovery following ex vivo I/R (59% of baseline vs. 29%). Mechanisms contributing to ischaemic protection in CrT-OE hearts include elevated PCr and glycogen levels and improved energy reserve. Furthermore, creatine loading in HL-1 cells did not alter antioxidant defences, but delayed mitochondrial permeability transition pore opening in response to oxidative stress, suggesting an additional mechanism to prevent reperfusion injury.


CONCLUSIONS
Elevation of myocardial creatine by 20-100% reduced myocardial stunning and I/R injury via pleiotropic mechanisms, suggesting CrT activation as a novel, potentially translatable target for cardiac protection from ischaemia.
Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. clygate@well.ox.ac.uk
Craig A
CA
Lygate
Steffen
S
Bohl
Michiel
M
ten Hove
Kiterie M E
KM
Faller
Philip J
PJ
Ostrowski
Sevasti
S
Zervou
Debra J
DJ
Medway
Dunja
D
Aksentijevic
Liam
L
Sebag-Montefiore
Julie
J
Wallis
Kieran
K
Clarke
Hugh
H
Watkins
Jürgen E
JE
Schneider
Stefan
S
Neubauer
D000818:Animals; D002460:Cell Line; D003401:Creatine / Q000378:metabolism*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D006003:Glycogen / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019028:Magnetic Resonance Imaging, Cine; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017682:Myocardial Stunning / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D018384:Oxidative Stress; D010725:Phosphocreatine / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C080679:creatine transporter; D010725:Phosphocreatine; D006003:Glycogen; D003401:Creatine