Abstract 542: Mice with Cardiomyocyte-Restricted IGF-1 Receptor Deletion Exhibit Diminished Cardiomyocyte Size and Resistance to Exercise-Induced Cardiac Hypertrophy
Insulin-like growth factor 1 (IGF-1) and IGF-1 receptors are expressed in murine hearts, and IGF-1 receptor signaling in cardiac muscle has been proposed to play a role in growth, differentiation, and cell survival, but mechanisms by which IGF-1 modulates myocardial structure and function are only partially understood. To investigate the role of IGF-1 signaling on cardiac development and physiology, we generated mice with cardiomyocyte-restricted knockout of the IGF-1receptor (IGF-1R −/−) by crossing α-MHC-Cre mice with mice containing a floxed exon 3 of the IGF-1R gene. Ablation of IGF-1 receptors in cardiomyocytes did not alter baseline heart weight to tibia length (HW/TL) ratios at 8 weeks or 12 weeks of age. However, wheat germ agglutinin (WGA-FITC) staining revealed that myocyte cross-sectional area was reduced by 18.8% (P < 0.05). To define the contribution of IGF-1 receptor signaling in the development of physiological hypertrophy; mice [WT (n = 7) or IGF-1R −/− (n = 9)] were subjected to 4 weeks swim (Sw) training and compared with Sedentary (Sed) wild type (WT) (n = 5) or IGF-1R −/− (n = 7) mice. HW/TL ratios increased by 19.2% in WT animals after swim training (5.19 ± 0.26 vs. 6.18 ± 0.2, P < 0.05), but only by 5.5% in Sw IGF-1R −/− mice (5.58 ± 0.18 vs. 5.89 ± 0.22, P = 0.32) and the fold increase in HW/TL was significantly greater in Sw WT vs. Sw IGF-1R −/− (P < 0.05). Despite resistance to hypertrophy, cardiac systolic function assessed by ejection fraction was preserved in Sw IGF-1R −/− (before Sw 0.71 ± 0.02 vs. after Sw 0.67 ± 0.02, P = 0.12). Phosphorylation of Akt was significantly increased in both trained WT and IGF-1R−/− mice at Ser473 [fold-change 1.61 ± 0.09 (P < 0.05) and 2.11 ± 0.19 (P < 0.01), respectively] and Thr308 [2.42 ± 0.24 and 2.61 ± 0.59 (P < 0.01), respectively] vs. Sed. Surprisingly Ser (473) Akt phosphorylation was greater in Sw IGF-1R−/− vs. Sw WT (P < 0.05). These data define an essential role for IGF-1 signaling in mediating physiologic cardiomyocyte hypertrophy, and indicate that although Akt signaling might be necessary for mediating physiological cardiac hypertrophy it is not sufficient in the absence of myocardial IGF-1R signaling.