Exploring the therapeutic potential of augmenting cardiac energetics

The energetic requirements of the heart are weight-for-weight higher than for any other organ. This is met by continuously recycling a relatively small pool of adenosine triphosphate (ATP), which drives almost all energy consuming processes in the cell. Maintaining adequate levels of ATP is therefore critically important and multiple mechanisms have evolved to ensure that supply meets demand. For example, the creatine kinase (CK) system acts as a spatial and temporal energy buffer with mitochondrial-CK (mito-CK) catalysing the transfer of a high-energy phosphoryl group from ATP onto creatine to form phosphocreatine (PCr) and ADP. PCr is then available for rapid regeneration of ATP catalysed by cytosolic CK dimers consisting of Muscle- (M-CK) and Brain- (B-CK) isoforms. ATP may also be generated via the activity of adenylate kinase (AK) which catalyses the reversible reaction 2ADP ↔ ATP + AMP. Recent experiments overexpressing key components of these phosphotransfer systems in mice show protection from acute ischaemia and chronic heart failure, suggesting this may be a useful new therapeutic strategy for these deadly conditions.


Our laboratory has recently generated novel transgenic models of CK and AK system augmentation that now need full characterisation from the molecular level to the whole organism. For example, a project might take one such model from initial biochemical validation to full in vivo cardiac phenotyping, leading to testing in clinically-relevant disease models. The project will further seek to contribute to our limited understanding of how creatine, CK and AK are regulated in normal physiology and disease, and in particular, the mechanisms leading to altered regulation in the failing heart. It is hoped that these insights will provide potential therapeutic targets for manipulation in vivo.