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Abstract
The aim of this work was to study whether changes in fructose 2,6-bisphosphate concentration are correlated with variations of the glycolytic flux in the isolated working rat heart. Glycolysis was stimulated to different extents by increasing the concentration of glucose, increasing the workload, or by the addition of insulin. The glycolytic flux was measured by the rate of detritiation of [2-3H]- and [3-3H]glucose. Under all the conditions tested, an increase in fructose 2,6-bisphosphate content was observed. The glucose- or insulin-induced increase in fructose 2,6-bisphosphate content was related to an increase in the concentration of fructose 6-phosphate, the substrate of 6-phosphofructo-2-kinase. An increase in the workload correlated with a 50% decrease in the Km of 6-phosphofructo-2-kinase for fructose 6-phosphate. Similar changes in Km have been observed when purified heart 6-phosphofructo-2-kinase was phosphorylated in vitro by the cyclic AMP-dependent protein kinase or by the calcium/calmodulin-dependent protein kinase. Since the concentration of cyclic AMP was not affected by increasing the workload, it is possible that the change in Km of 6-phosphofructo-2-kinase, which was found in hearts submitted to a high load, resulted from phosphorylation by calcium/calmodulin protein kinase; other possibilities are not excluded. Anoxia decreased the external work developed by the heart, stimulated glycolysis and glycogenolysis, but did not increase fructose 2,6-bisphosphate.
Highlights
Increase bothglycolysis and Fru-2,6-P2 concentration in heart by an activation of 6-phosphofructo-2-kinase(PFK-2), the enzyme responsible for the synthesis of Fru-2,6-P2, with no significant change in the activitoyf fructose-2,6-bisphosphatase (FBPase-X), the enzyme which hydrolyzes Fru-2,6-Pz (2, 4, 5, 8, 9)
We have studied whether variations in Fru2,6-P2 content could be related to changes in glycolysis induced byaltering theglucose load or theworkload, by addition of insulin or by anoxia
Stimulation of Glycolysis by Workload-When the workload applied to the hearts perfused with 11 mM glucose was increased, the external work, expressed as a hydraulic power, was more than doubled,as was the rate of oxygen consumption (Table I)
Summary
Increase bothglycolysis and Fru-2,6-P2 concentration in heart by an activation of 6-phosphofructo-2-kinase(PFK-2), the enzyme responsible for the synthesis of Fru-2,6-P2, with no significant change in the activitoyf fructose-2,6-bisphosphatase (FBPase-X), the enzyme which hydrolyzes Fru-2,6-Pz (2, 4, 5 , 8, 9). Bothincreased workload (10-12) and anoxia (13) are known to stimulate glycolysis in the heart. Whether these conditions are related toa change in Fru-2,6-P2 has not been studied. The effect of workload variation by itself on Fru-2,6-P2 content has not been reportaedc,omparison of “Langendorff-perfused” hearts with working hearts indicated that glycolysis and Fru-2,6-P2 concentration were both increased in the latter system( 5 ). We have studied whether variations in Fru2,6-P2 content could be related to changes in glycolysis induced byaltering theglucose load or theworkload, by addition of insulin or by anoxia. Fructose2,6-bisphosphate(Fru-2,6-Pz)lisanubiquitous stimulator of 6-phosphofructo-1-kinase(PFK-l), a key enzyme of glycolysis, and can be regarded as an intracellular signal that controls glycolysis (1).In Langendorff-perfused rat hearts,a glucose-dependent increase inFru-2,6-P2 concentration has been reported (2). Two workload conditions were chosen; for the low load, both the preload and the afterload were low (5 and 60 cm of water, respectively); for the high load, both the preload and the afterload were increased to 15 and 120 cm of water, respectively
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