AMP-activated protein kinase (AMPK) is an energysensing enzyme that plays a pivotal role in regulating 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 ␣2 catalytic subunit to clarify the functional role of this kinase in myocardial ischemia. In isolated perfused hearts subjected to a 10-min ischemia, AMPK ␣2 activity in wild type (WT) increased substantially (by 4.5-fold), whereas AMPK ␣2 activity in TG was similar to the level of WT at base line. Basal AMPK ␣1 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 ␣2 in TG significantly blunted this response. Using 31 P 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 ␣2 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.The AMP-activated protein kinase (AMPK) 1 functions as a fuel gauge, such that when the cell is exposed to stresses associated with energy depletion, it switches off ATP-utilizing pathways and switches on ATP-generating pathways to restore energy homeostasis (1, 2). This kinase is activated by decreases in ATP/AMP and in phosphocreatine (PCr)/creatine through Thr 172 phosphorylation by one or more upstream kinases (AMPK kinase) and through allosteric modification by AMP (1, 2). AMPK is a heterotrimeric protein consisting of a catalytic subunit (␣) and two regulatory subunits ( and ␥) (1, 3). Each subunit has two or more different isoforms; the ␣1 subunit is widely expressed, whereas the ␣2 subunit is expressed primarily in liver, heart, and skeletal muscle (2, 4, 5).It has been suggested that AMPK regulates glucose and fatty acid metabolism in striated muscles (6, 7). Studies from our groups and others showed increased AMPK activity during acute and chronic stresses, such as hypoxia and exercise in skeletal muscle and ischemia and pressure overload in the heart (8 -12). Activation of AMPK in the heart is associated with enhanced glucose uptake and glycolysis (10, 11, 13). As glycolysis is a major source of ATP during ischemia, stimulation of glucose uptake and glycolysis by AMPK in the ischemic heart is consistent ...
Background-Downregulation of peroxisome proliferator-activated receptor-␣ (PPAR␣) in hypertrophied and failing hearts leads to the reappearance of the fetal metabolic pattern, ie, decreased fatty acid oxidation and increased reliance on carbohydrates. Here, we sought to elucidate the functional significance of this shift in substrate preference. Methods and Results-We assessed contractile function and substrate utilization using 13 C nuclear magnetic resonance spectroscopy and high-energy phosphate metabolism using 31 P nuclear magnetic resonance spectroscopy in perfused hearts isolated from genetically modified mice (PPAR␣ Ϫ/Ϫ ) that mimic the metabolic profile in myocardial hypertrophy. We found that the substrate switch from fatty acid to glucose (3-fold down) and lactate (3-fold up) in PPAR␣ Ϫ/Ϫ hearts was sufficient for sustaining normal energy metabolism and contractile function at baseline but depleted the metabolic reserve for supporting high workload. Decreased ATP synthesis (measured by 31 P magnetization transfer) during high workload challenge resulted in progressive depletion of high-energy phosphate content and failure to sustain high contractile performance. Interestingly, the metabolic and functional defects in PPAR␣ Ϫ/Ϫ hearts could be corrected by overexpressing the insulin-independent glucose transporter GLUT1, which increased the capacity for glucose utilization beyond the intrinsic response to PPAR␣ deficiency.Conclusions-These findings demonstrate that metabolic remodeling in hearts deficient in PPAR␣ increases the susceptibility to functional deterioration during hemodynamic overload. Moreover, our results suggest that normalization of myocardial energetics by further enhancing myocardial glucose utilization is an effective strategy for preventing the progression of cardiac dysfunction in hearts with impaired PPAR␣ activity such as hearts with pathological hypertrophy.
A solution-derived NiOx film was successfully employed to work as the hole selective contact for a high efficiency inverted planar heterojunction perovskite solar cell with negligible hysteresis.
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