Insulin signaling is critical for sinoatrial node maintenance and function

초록

Insulin signaling: A role in controlling heart rateThe hormone insulin and the related protein insulin-like growth factor-1 (IGF-1) have previously unrecognized significance in regulating heart rate through cell signaling activities affecting the pacemaker region of the heart. Researchers in South Korea led by Wang-Soo Lee and Jaetaek Kim at Chung-Ang University, Seoul, investigated the role of receptor proteins that bind to insulin and IGF-1 in the heart's pacemaker sinoatrial node in mice. They explored the effects of genetic interventions altering the normal levels of these receptor proteins, revealing a critical role for insulin and IGF-1 in sinoatrial node function. The results could suggest new approaches to treating sinus node dysfunction (SND), also known as sick sinus syndrome. SND is associated with increased risk of fainting, atrial fibrillation and heart failure, especially in elderly or overweight people. Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cellular growth and glucose metabolism in the myocardium. However, their physiological role in the cells of the cardiac conduction system has never been explored. Therefore, we sought to determine the spatiotemporal function of insulin/IGF-1 receptors in the sinoatrial node (SAN). 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. Telemetric electrocardiography revealed 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 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 revealed 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 their sinus node dysfunction. Our results reveal a previously unrecognized role of insulin/IGF-1 signaling in sinus node structural maintenance and pacemaker function.

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