Abstract 394: Hypertrophy in GLUT4 Deficient Hearts Results From Increased Sensitivity of mTOR Signaling
Cardiac specific ablation of GLUT4 glucose transporters (G4KO) leads to compensated hypertrophy, but the mechanisms responsible are unknown. Mammalian target of rapamycin (mTOR) plays an important role in the induction and maintenance of pathologic and physiologic cardiac hypertrophy. We therefore sought to determine the role of mTOR in the induction and maintenance of cardiac hypertrophy in G4KO mice. Because nutrients are important regulators of mTOR, G4KO and WT mice were subjected to modest nutritional deprivation between birth and weaning (4 weeks). Caloric restriction (CR) resulted in growth retardation in WT and G4KO mice. Body weights decreased by 16%, p<0.02 in WT and 27%, p<0.001 in G4KO relative to nutritionally replete (fed) mice. HW: Tibia length (HW: TL) was increased by 18% in fed G4KO vs. fed WT. CR had no effect on heart size in WT mice, but in G4KO mice CR prevented hypertrophy, so that HW: TL was identical to that of fed and CR WT mice. To further evaluate the role of mTOR in established hypertrophy of G4KO hearts, 13-week old G4KO and WT mice were treated with Rapamycin (Rap) or vehicle for 4 weeks. In non-treated hearts HW: TL was 45% greater in G4KO. Rap treatment reduced HW: TL by 25% in G4KO and by 15% in WT. HW: TL in Rap treated G4KO was equal to non treated WT and 17% greater than Rap treated WT. We then subjected G4KO and WT mice to a short-term hypertrophic challenge with isoproterenol (ISO) 17mg/kg for 60 hrs. ISO increased HW: TL by 28% in G4KO (p<0.0003) and by 20% in WT (p<0.04). Rap treatment completely prevented the hypertrophic response of G4KO hearts and had a non significant effect on WT hearts. In summary:
perinatal nutritional deprivation prevents cardiac hypertrophy in G4KO mice,
mTOR inhibition causes significant but partial regression of established hypertrophy in adult G4KO mice,
In contrast to WT, G4KO have a more robust hypertrophic response to short term adrenergic challenge that is completely prevented by mTOR inhibition.
Thus the metabolic disturbance caused by GLUT4 deletion in the heart increases the sensitivity of mTOR mediated hypertrophic signaling pathways.