Insulin signaling is critical for sinoatrial node maintenance and function

Abstract

Abstract Background Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cellular growth and glucose metabolism in the myocardium. However, their physiological role in cardiac conduction cells has never been explored. Therefore, we sought to determine the spatiotemporal function of insulin/IGF-1 receptors in the sinoatrial node (SAN). Methods We generated cardiac conduction cell-specific inducible IGF-1 receptor (IGF-1R) knockout (KO) (CSIGF1RKO), insulin receptor (IR) KO (CSIRKO), and IR/IGF-1R double KO (CSDIRKO) mice and evaluated their phenotypes. Results Telemetry measured electrocardiography found regular sinus rhythm in CSIGF1RKO mice, indicating that IGF-1R is dispensable for normal pacemaking. In contrast, CSIRKO and CSDIRKO mice exhibited profound sinus bradycardia. CSDIRKO mice showed a typical sinus node dysfunction characterized by junctional rhythm and sinus pauses on electrocardiography. Interestingly, the lack of an insulin receptor in the SAN cells of CSIRKO and CSDIRKO mice caused sinus nodal fibrosis. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) protein expression significantly decreased in the CSIRKO and CSDIRKO mice relative to the controls. A patch-clamp study of the SAN cells of CSIRKO mice marked a significant decrease in the funny current, which is responsible for spontaneous diastolic depolarization in the SAN. This result suggested that insulin receptor loss reduces the heart rate via downregulation of the HCN4 channel. Additionally, HCN1 expression was decreased in CSDIRKO mice explaining sinus node dysfunction. Conclusion Our results reveal a previously unrecognized insulin/IGF-1 signaling role in the sinus node structural maintenance and pacemaker function.