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 language | English (US) |
|---|---|
| Pages (from-to) | 28372-28377 |
| Number of pages | 6 |
| Journal | Journal of Biological Chemistry |
| Volume | 278 |
| Issue number | 31 |
| DOIs | |
| State | Published - Aug 1 2003 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative α2 subunit of AMP-activated protein kinase. / Xing, Yanqiu; Musi, Nicolas; Fujii, Nobuharu; Zou, Liqun; Luptak, Ivan; Hirshman, Michael F.; Goodyear, Laurie J.; Tian, Rong.
In: Journal of Biological Chemistry, Vol. 278, No. 31, 01.08.2003, p. 28372-28377.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative α2 subunit of AMP-activated protein kinase
AU - Xing, Yanqiu
AU - Musi, Nicolas
AU - Fujii, Nobuharu
AU - Zou, Liqun
AU - Luptak, Ivan
AU - Hirshman, Michael F.
AU - Goodyear, Laurie J.
AU - Tian, Rong
PY - 2003/8/1
Y1 - 2003/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0041707843&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0041707843&partnerID=8YFLogxK
U2 - 10.1074/jbc.M303521200
DO - 10.1074/jbc.M303521200
M3 - Article
C2 - 12766162
AN - SCOPUS:0041707843
VL - 278
SP - 28372
EP - 28377
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 31
ER -