Glucose 6-Phosphate Accumulates via Phosphoglucose Isomerase Inhibition in Heart Muscle.

Rationale: Metabolic and structural remodeling is a hallmark of heart failure. This remodeling involves activation of the mammalian target of rapamycin (mTOR) signaling pathway, but little is known on how intermediary metabolites are integrated as metabolic signals. Objective: We investigated the metabolic control of cardiac glycolysis and explored the potential of glucose 6-phosphate to regulate glycolytic flux and mTOR activation. Methods and Results: We developed a kinetic model of cardiomyocyte carbohydrate metabolism, CardioGlyco, to study the metabolic control of myocardial glycolysis and glucose 6-phosphate levels. Metabolic control analysis revealed that glucose 6-phosphate concentration is dependent on phosphoglucose isomerase activity. Next, we integrated ex vivo tracer studies with mathematical simulations to test how changes in glucose supply and glycolytic flux affect mTOR activation. Nutrient deprivation promoted a tight coupling between glucose uptake and oxidation, glucose 6-phosphate reduction, and increased protein-protein interaction between hexokinase II and mTOR. We validated the in silico modeling in cultured adult mouse ventricular cardiomyocytes by modulating phosphoglucose isomerase activity using erythrose 4-phosphate. Inhibition of glycolytic flux at the level of phosphoglucose isomerase caused glucose 6-phosphate accumulation, which correlated with increased mTOR activation. Using click chemistry, we labeled newly synthesized proteins and confirmed that inhibition of phosphoglucose isomerase increases protein synthesis. Conclusions: The reduction of phosphoglucose isomerase activity directly affects myocyte growth by regulating mTOR activation.