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.