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Adenylate kinase-catalyzed phosphotransfer in the myocardium : increased contribution in heart failure
P P Dzeja1, K T Vitkevicius, M M Redfield
1Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
Insights
Adenylate kinase plays a crucial role in heart energy transfer, compensating for reduced creatine kinase activity in heart failure. This pathway supports myocardial bioenergetics and contractile function during cardiac stress.
Area of Science:
- Biochemistry
- Cardiology
- Cellular Energetics
Background:
- Creatine kinase downregulation is linked to heart failure, yet some hearts maintain function, suggesting alternative energy pathways.
- The specific phosphotransfer mechanisms compensating for creatine kinase in the heart remain largely unidentified.
Purpose of the Study:
- To investigate the role of adenylate kinase-catalyzed phosphotransfer in myocardial energetics.
- To quantify adenylate kinase's contribution to energy transfer in normal and failing hearts.
Main Methods:
- Utilized isolated mitochondria/actomyosin systems to assess adenylate kinase activity and its impact on contraction.
- Employed 18O-phosphoryl labeling with gas chromatography-mass spectrometry in intact myocardium to measure phosphotransfer rates.
- Studied pacing-induced heart failure models in myocardium.
Main Results:
- Adenylate kinase activity directly supports actomyosin contraction and mitochondrial respiration, indicating its role in energy flow.
- In normal hearts, adenylate kinase contributes 10% to ATP turnover, while creatine kinase contributes 89%.
- In heart failure, adenylate kinase phosphotransfer increases by 134% (contributing 21% to ATP turnover), as creatine kinase contribution drops to 40%.
Conclusions:
- Adenylate kinase facilitates high-energy phosphoryl transfer and communication between mitochondria and myofibrils in cardiac muscle.
- Adenylate kinase serves as a compensatory mechanism in heart failure, maintaining ATP turnover despite reduced creatine kinase activity.
- This highlights adenylate kinase's importance in myocardial bioenergetics and cardiac function during disease.
Abstract:
Although the downregulation of creatine kinase activity has been associated with heart failure, creatine kinase-deficient transgenic hearts have a preserved contractile function. This suggests the existence of alternative phosphotransfer pathways in the myocardium, the identity of which is still unknown. In this study, we examined the contribution of adenylate kinase-catalyzed phosphotransfer to myocardial energetics. In the isolated mitochondria/actomyosin system, which possesses endogenous adenylate kinase activity in both compartments, substrates for adenylate kinase promoted the rate and amplitude of actomyosin contraction that was further enhanced by purified adenylate kinase. Inhibition of adenylate kinase activity diminished both actomyosin contraction and mitochondrial respiration, which indicated reduced energy flow between mitochondria and myofibrils. In intact myocardium, the net adenylate kinase-catalyzed phosphotransfer rate was 10% of the total ATP turnover rate as measured by 18O-phosphoryl labeling in conjunction with gas chromatography and mass spectrometry. In pacing-induced failing heart, adenylate kinase-catalyzed phosphotransfer increased by 134% and contributed 21% to the total ATP turnover. Concomitantly, the contribution by creatine kinase dropped from 89% in normal hearts to 40% in failing hearts. These phosphotransfer changes were associated with reduced levels of metabolically active ATP but maintained overall ATP turnover rate. Thus, this study provides evidence that adenylate kinase facilitates the transfer of high-energy phosphoryls and signal communication between mitochondria and actomyosin in cardiac muscle, with an increased contribution to cellular phosphotransfer in heart failure. This phosphotransfer function renders adenylate kinase an important component for optimal myocardial bioenergetics and a compensatory mechanism in response to impaired intracellular energy flux in the failing heart.