Roles of the creatine kinase system and myoglobin in maintaining energetic state in the working heart

<p>Abstract</p> <p>Background</p> <p>The heart is capable of maintaining contractile function despite a transient decrease in blood flow and increase in cardiac ATP demand during systole. This study analyzes a previously developed model of cardiac energetics and oxygen transport to understand the roles of the creatine kinase system and myoglobin in maintaining the ATP hydrolysis potential during beat-to-beat transient changes in blood flow and ATP hydrolysis rate.</p> <p>Results</p> <p>The theoretical investigation demonstrates that elimination of myoglobin only slightly increases the predicted range of oscillation of cardiac oxygenation level during beat-to-beat transients in blood flow and ATP utilization. In silico elimination of myoglobin has almost no impact on the cytoplasmic ATP hydrolysis potential (Δ<it>G</it>_ATPase). In contrast, disabling the creatine kinase system results in considerable oscillations of cytoplasmic ADP and ATP levels and seriously deteriorates the stability of Δ<it>G</it>_ATPasein the beating heart.</p> <p>Conclusion</p> <p>The CK system stabilizes Δ<it>G</it>_ATPaseby both buffering ATP and ADP concentrations and enhancing the feedback signal of inorganic phosphate in regulating mitochondrial oxidative phosphorylation.</p

The Myocardial Creatine Kinase System in the Normal, Ischaemic and Failing Heart

The creatine kinase (CK) system is the final step in cardiac energy metabolism providing a direct link between energy production in the mitochondria and energy utilising ATPases. It acts as an energy storage and transport mechanism and maintains favourable local ATP/ADP ratios, thereby supporting further energy production and high levels of free energy from ATP hydrolysis. Down-regulation of CK activity and myocardial creatine levels is a universal finding in chronic heart failure, and the degree of impairment has been shown to be an excellent prognostic indicator in patients. However, it is unclear whether these changes represent epiphenomenon or contribute to disease pathophysiology. This chapter focuses on attempts over the past 20 years to address this question using genetic loss-of-function models in the mouse. Findings from these models have been equivocal and at times contradictory, however, recent evidence suggests that loss of creatine or CK is not detrimental in surgical models of chronic heart failure, providing the clearest evidence to date that such changes do not contribute to dysfunction. Despite this conclusion, over-expression of CK in mouse heart has been found to protect against heart failure and improve survival. In the setting of ischaemia-reperfusion injury, loss of creatine or CK impairs functional recovery and augmentation of either is cardioprotective. We are therefore entering an exciting new era of research in this field aimed at understanding the benefits of CK system augmentation and identifying new mechanisms to achieve this without genetic modification for possible future clinical translation