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Am J Physiol Heart Circ Physiol 297: H313-H321, 2009. First published May 8, 2009; doi:10.1152/ajpheart.01298.2008
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Suppression of 5'-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts

Clifford D. L. Folmes,1 Cory S. Wagg,1 Mei Shen,2 Alexander S. Clanachan,1 Rong Tian,2 and Gary D. Lopaschuk1

1Cardiovascular Research Group and Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada; and 2NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Submitted 16 December 2008 ; accepted in final form 27 April 2009

Activation of 5'-AMP-activated protein kinase (AMPK) may benefit the heart during ischemia-reperfusion by increasing energy production. While AMPK stimulates glycolysis, mitochondrial oxidative metabolism is the major source of ATP production during reperfusion of ischemic hearts. Stimulating AMPK increases mitochondrial fatty acid oxidation, but this is usually accompanied by a decrease in glucose oxidation, which can impair the functional recovery of ischemic hearts. To examine the relationship between AMPK and cardiac energy substrate metabolism, we subjected isolated working mouse hearts expressing a dominant negative (DN) {alpha}2-subunit of AMPK (AMPK-{alpha}2 DN) to 20 min of global no-flow ischemia and 40 min of reperfusion with Krebs-Henseleit solution containing 5 mM [U-14C]glucose, 0.4 mM [9, 10-3H]palmitate, and 100 µU/ml insulin. AMPK-{alpha}2 DN hearts had reduced AMPK activity at the end of reperfusion (82 ± 9 vs. 141 ± 7 pmol·mg–1·min–1) with no changes in high-energy phosphates. Despite this, AMPK-{alpha}2 DN hearts had improved recovery of function during reperfusion (14.9 ± 0.8 vs. 9.4 ± 1.4 beats·min–1·mmHg·10–3). During reperfusion, fatty acid oxidation provided 44.0 ± 2.8% of total acetyl-CoA in AMPK-{alpha}2 DN hearts compared with 55.0 ± 3.2% in control hearts. Since insulin can inhibit both AMPK activation and fatty acid oxidation, we also examined functional recovery in the absence of insulin. Functional recovery was similar in both groups despite a decrease in AMPK activity and a decreased reliance on fatty acid oxidation during reperfusion (66.4 ± 9.4% vs. 85.3 ± 4.3%). These data demonstrate that the suppression of cardiac AMPK activity does not produce an energetically compromised phenotype and does not impair, but may in fact improve, the recovery of function after ischemia.

ischemia-reperfusion; fatty acid oxidation; glycolysis; glucose oxidation


Address for reprint requests and other correspondence: G. D. Lopaschuk, Univ. of Alberta, 423 Heritage Medical Research Bldg., Edmonton, AB, Canada T6G 2S2 (e-mail: gary.lopaschuk{at}ualberta.ca)






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