Responses of GLUT4-Deficient Hearts to Ischemia Underscore the Importance of Glycolysis

Abstract

Background —The ischemic heart is dependent on glycolysis for ATP generation, and therapies that increase glucose utilization during ischemia improve survival. Myocardial ischemia results in the translocation of the glucose transporter proteins GLUT1 and GLUT4 to the sarcolemma. The increased glucose entry via these transporters contributes to enhanced glycolysis during ischemia. Methods and Results —To determine the role of GLUT4 in mediating increased glycolytic flux during ischemia, hearts from mice with cardiac-selective GLUT4 deficiency (G4H−/−) were subjected to global low-flow ischemia. During normal perfusion, hearts from fed G4H−/− mice showed increased GLUT1-mediated glucose uptake, higher concentrations of glycogen and phosphocreatine, but delayed recovery after ischemia. When these compensatory changes were eliminated by a 20-hour fast, G4H−/− hearts exhibited depressed glucose utilization during ischemia and developed profound and irreversible systolic and diastolic dysfunction associated with accelerated ATP depletion during ischemia and diminished regeneration of high-energy phosphate compounds on reperfusion. Conclusions —GLUT4 is an important mediator of enhanced glycolysis during ischemia and represents an important protective mechanism against ischemic injury.