Rapid Changes in Carbohydrate Metabolism in Muscle Induced by Triiodothyronine; the Role of Glucose 1,6-Bisphosphate

Abstract

All of the past research on glucose utilization by muscles focused on the slow action of thyroid hormones. Here we show that experimental hyperthyroidism, which was induced in rats by a single intramuscular injection of 3,3′,5-triiodothyronine (T3) at high concentrations, resulted in rapid changes (within minutes) in carbohydrate metabolism in tibialis anterior muscle, There was an increase in lactate content, in the allosteric activity of soluble phosphofructokinase (the rate-limiting enzyme in glycolysis), and in its product fructose 1,6-bisphosphate, 5 min following the injection of T3, suggesting stimulation of glycolysis. The allosteric activity of mitochondrial-bound, and, to a lesser extent, of soluble hexokinase, was also enhanced. However, the intracellular distribution of the enzymes was unchanged by the hormone. The allosteric stimulation of hexokinase may be attributed to the decrease in glucose 1,6-bisphosphate, which is a potent inhibitor of hexokinase. The level of glucose 6-phosphate, another known inhibitor of hexokinase, was not changed by the hormone. The activation of phosphofructokinase following T3 injection may be attributed to the decrease in ATP, an allosteric inhibitor of the enzyme, and the increase in the levels of Pi and fructose 1,6-bisphosphate, allosteric activators of the enzyme. Glycogen content was also significantly decreased in muscle 5 min following the injection of T3. These results suggest that in hyperthyroidism, muscle reacts rapidly to the excess of thyroid hormones by stimulation of glycogenolysis, glucose phosphorylation, and glycolysis, to provide ATP, which may serve as a compensatory mechanism to ATP depletion.