Adam R Wende, Jaetaek Kim, William L Holland, Benjamin E Wayment, Brian T O'Neill, Joseph Tuinei, Manoja K Brahma, Mark E Pepin, Mark A McCrory, Ivan Luptak, Ganesh V Halade, Sheldon E Litwin, E Dale Abel

Pathological cardiac hypertrophy may be associated with reduced expression of the GLUT4 glucose transporter in contrast to exercise-induced cardiac hypertrophy, where GLUT4 levels are increased. However, mice with cardiac specific deletion of GLUT4 (G4H-/-) have normal cardiac function in the unstressed state. This study tested the hypothesis that cardiac GLUT4 is required for myocardial adaptations to hemodynamic demands. G4H-/- and control littermates (Con) were subjected to either a pathological model of left ventricular pressure overload (transverse aortic constriction; TAC) or a physiological model of endurance exercise (swim training). As predicted following TAC, G4H-/- mice developed significantly greater hypertrophy and more severe contractile dysfunction. Somewhat surprisingly, after exercise training, G4H-/- mice developed increased fibrosis and apoptosis that was associated with dephosphorylation of the pro-survival kinase Akt in concert with an increase in protein levels of the upstream phosphatase, PP2A. Exercise has been shown to decrease levels of ceramide, G4H-/- hearts failed to decrease myocardial ceramide in response to exercise. Furthermore, G4H-/- hearts have reduced levels of the transcriptional co-activator PGC-1, lower CPT activity, and reduced HADH activity. These basal changes may also contribute to the impaired ability of G4H-/- hearts to adapt to hemodynamic stresses. In conclusion, GLUT4 is required for the maintenance of cardiac structure and function in response to physiological or pathological processes that increase energy demands, in part through secondary changes in mitochondrial metabolism and cellular stress survival pathways such as Akt.