Insulin-Like Growth Factor I Receptor Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

Abstract

The receptors for IGF-I (IGF-IR) and insulin (IR) have been implicated in physiological cardiac growth, but it is unknown whether IGF-IR or IR signaling are critically required. We generated mice with cardiomyocyte-specific knockout of IGF-IR (CIGF1RKO) and compared them with cardiomyocyte-specific insulin receptor knockout (CIRKO) mice in response to 5 wk exercise swim training. Cardiac development was normal in CIGF1RKO mice, but the hypertrophic response to exercise was prevented. In contrast, despite reduced baseline heart size, the hypertrophic response of CIRKO hearts to exercise was preserved. Exercise increased IGF-IR content in control and CIRKO hearts. Akt phosphorylation increased in exercise-trained control and CIRKO hearts and, surprisingly, in CIGF1RKO hearts as well. In exercise-trained control and CIRKO mice, expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and glycogen content were both increased but were unchanged in trained CIGF1RKO mice. Activation of AMP-activated protein kinase (AMPK) and its downstream target eukaryotic elongation factor-2 was increased in exercise-trained CIGF1RKO but not in CIRKO or control hearts. In cultured neonatal rat cardiomyocytes, activation of AMPK with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) prevented IGF-I/insulin-induced cardiomyocyte hypertrophy. These studies identify an essential role for IGF-IR in mediating physiological cardiomyocyte hypertrophy. IGF-IR deficiency promotes energetic stress in response to exercise, thereby activating AMPK, which leads to phosphorylation of eukaryotic elongation factor-2. These signaling events antagonize Akt signaling, which although necessary for mediating physiological cardiac hypertrophy, is insufficient to promote cardiac hypertrophy in the absence of myocardial IGF-I signaling.

A Novel Cardiomyocyte-enriched MicroRNA, miR-378, Targets Insulin-like Growth Factor 1 Receptor

“…In transgenic mice, cardiacspecific overexpression of IGR1R triggered myocyte hypertrophy and enhanced systolic function (23). IGF1R signaling is also found to be essential in inducing physiological growth associated with exercise-induced cardiac hypertrophy (24). Exogenous administration of IGF1 in vivo reduces cardiomyocyte apoptosis in response to stress injury (25)(26)(27)(28).…”

IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

“…Hepatocytes express little IGF-1R and receptor abundance in liver is relatively low. 32 However, high levels of IGF-I production, together with increased expression of IGF-1R and IGF-II after BDL are sufficient for significant biological effects. To study the consequences of IGF-1R loss-of-function, we inactivated the Igf1r gene in hepatocytes.…”

Cardiac hypertrophy and IGF-1 response to testosterone propionate treatment in trained male rats

“…The results of previous studies suggested that endurance training of laboratory animals increased myocardial expression of IGF-1, leading to cardiac hypertrophy [6,7,17]. The hypothesis of the major role of IGF-1 as a paracrine/autocrine factor regulating myocardial remodeling is lent support by data on aorta-coronary sinus IGF-1 concentrations in elite male athletes [18].…”

“…Several studies confirmed an important role of anabolic steroids in IGF-1 production and IGF-1 mRNA expression in the myocardium [6,7,19,24]. IGF-1 is an important growth factor which, via its receptors, mediates physiological cardiac growth and cell differentiation by the activation of phosphoinositide 3-kinase (PI-3K) and mitogen-activated protein kinase (MAPK) signaling pathways.…”

“…The mechanical loading regulates intracellular signals of specific gene expression for myocardial hypertrophy with participation of both endocrine and paracrine factors [6,7,8].…”