Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative α2 subunit of AMP-activated protein kinase

Yanqiu Xing, Nicolas Musi, Nobuharu Fujii, Liqun Zou, Ivan Luptak, Michael F. Hirshman, Laurie J. Goodyear, Rong Tian

Research output: Contribution to journalArticlepeer-review

175 Scopus citations

Abstract

AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that plays a pivotal role in regulating f cellular metabolism for sustaining energy homeostasis under stress conditions. Activation of AMPK has been observed in the heart during acute and chronic stresses, but its functional role has not been completely understood because of the lack of effective activators and inhibitors of this kinase in the heart. We generated transgenic mice (TG) with cardiac-specific overexpression of a dominant negative mutant of the AMPK α2 catalytic subunit to clarify the functional role of this kinase in myocardial ischemia. In isolated perfused hearts subjected to a 10-min ischemia, AMPK α2 activity in wild type (WT) increased substantially (by 4.5-fold), whereas AMPK α2 activity in TG was similar to the level of WT at base line. Basal AMPK α1 activity was unchanged in TG and increased normally during ischemia. Ischemia stimulated a 2.5-fold increase in 2-deoxyglucose uptake over base line in WT, whereas the inactivation of AMPK α2 in TG significantly blunted this response. Using 31P NMR spectroscopy, we found that ATP depletion was accelerated in TG hearts during no-flow ischemia, and these hearts developed left ventricular dysfunction manifested by an early and more rapid increase in left ventricular end-diastolic pressure. The exacerbated ATP depletion could not be attributed to impaired glycolytic ATP synthesis because TG hearts consumed slightly more glycogen during this period of no-flow ischemia. Thus, AMPK α2 is necessary for maintaining myocardial energy homeostasis during ischemia. It is likely that the functional role of AMPK in myocardial energy metabolism resides both in energy supply and utilization.

Original languageEnglish (US)
Pages (from-to)28372-28377
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number31
DOIs
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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