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1 Division of Cardiovascular Diseases, Departments of Medicine and Molecular Pharmacology and Experimental Therapeutics, and 2 Department of Biochemistry and Molecular Biology, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905; and 3 Center for Molecular Life Sciences, University Medical Center, University of Nijmegen, Nijmegen 6500, The Netherlands
Deletion of the major
adenylate kinase AK1 isoform, which catalyzes adenine nucleotide
exchange, disrupts cellular energetic economy and compromises metabolic
signal transduction. However, the consequences of deleting the
AK1 gene on cardiac energetic dynamics and performance in
the setting of ischemia-reperfusion have not been determined.
Here, at the onset of ischemia, AK1 knockout mice hearts
displayed accelerated loss of contractile force compared with wild-type
controls, indicating reduced tolerance to ischemic stress. On
reperfusion, AK1 knockout hearts demonstrated reduced nucleotide
salvage, resulting in lower ATP, GTP, ADP, and GDP levels and an
altered metabolic steady state associated with diminished
ATP-to-Pi and creatine phosphate-to-Pi ratios. Postischemic AK1 knockout hearts maintained ~40% of
-phosphoryl turnover, suggesting increased phosphotransfer flux
through remaining adenylate kinase isoforms. This was associated with
sustained creatine kinase flux and elevated cellular
glucose-6-phosphate levels as the cellular energetic system adapted to
deletion of AK1. Such metabolic rearrangements, along with sustained
ATP-to-ADP ratio and total ATP turnover rate, maintained
postischemic contractile recovery of AK1 knockout hearts at
wild-type levels. Thus deletion of the AK1 gene reveals that
adenylate kinase phosphotransfer supports myocardial function on
initiation of ischemic stress and safeguards intracellular
nucleotide pools in postischemic recovery.
energy metabolism; adenine nucleotides; glycolysis; phosphotransfer; oxygen-18 phosphoryl labeling; phosphorus-31 nuclear magnetic resonance
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