Abstract 2945: Conditional Deletion of the Insulin Receptor Gene in the Adult Heart Results in Myocyte Atrophy and Contractile Dysfunction Associated With the Induction of Autophagy
Background: Insulin/IGF-PI3K-Akt signaling axis regulates cardiac growth and contractile function. Cardiac-specific insulin receptor (IR) knockout mice exhibit 20% reduction in heart size with maintained contractility. This relatively mild phenotype may be in part due to compensatory mechanisms during embryonic and postnatal development. To further explore the role of myocardial insulin signaling, we analyzed inducible cardiac-specific IR knockout (iCIRKO) mice in which Ir gene was conditionally deleted in the adult heart.
Methods and Results: Irflox/flox mice were crossed with αMHC-MCM (tamoxifen-inducible form of Cre recombinase) transgenic mice, and inducible Ir gene disruption in the heart was achieved by tamoxifen treatment of Irflox/flox αMHC-MCM+/− mice. There was a progressive decline in heart weight/body weight ratio, ventricular wall thickness, myocyte cross-sectional area, and contractile function following conditional Ir deletion in the heart, which was associated with an increase in ANF expression, interstitial fibrosis, and connective tissue growth factor expression. Although myocyte atrophy and contractile dysfunction were evident in iCIRKO mice, muscle-specific E3 ubiquitin ligases (atrogin-1 and MuRF) were not induced and there was no significant increase in myocyte apoptosis. On the other hand, induction of autophagy was demonstrated by increased conversion of LC-3I to LC3-II and autophagosome formation.
Conclusion: Myocardial insulin signaling is essential for the maintenance of structural and functional homeostasis of the adult heart, and inactivation of this signaling pathway leads to myocyte atrophy and contractile dysfunction.