Insulin signaling is critical for sinoatrial node maintenance and function

Area of Science:

• Cardiovascular Physiology
• Endocrinology
• Molecular Cardiology

Background:

• Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cardiac growth and metabolism.
• The role of these signaling pathways in the cardiac conduction system, specifically the sinoatrial node (SAN), remains unexplored.

Purpose of the Study:

• To investigate the spatiotemporal function of insulin and IGF-1 receptors in the SAN.
• To determine the impact of receptor loss on SAN structure and function.

Main Methods:

• Generation of cardiac conduction cell-specific inducible knockout mouse models: IGF-1 receptor (IGF-1R) KO (CSIGF1RKO), insulin receptor (IR) KO (CSIRKO), and IR/IGF-1R double-KO (CSDIRKO).
• Phenotypic evaluation using telemetric electrocardiography and electrophysiological studies (patch-clamp).
• Assessment of protein expression, including hyperpolarization-activated cyclic nucleotide-gated channels (HCN4 and HCN1).

Main Results:

• IGF-1R is dispensable for normal SAN pacemaking; CSIGF1RKO mice maintained regular sinus rhythm.
• Loss of IR (CSIRKO) or both IR and IGF-1R (CSDIRKO) resulted in profound sinus bradycardia and sinus node dysfunction.
• CSIRKO and CSDIRKO mice exhibited SAN fibrosis, decreased HCN4 protein expression, and reduced funny current, indicating insulin receptor's role in SAN structural maintenance and pacemaker function via HCN4 regulation. HCN1 expression was also decreased in CSDIRKO mice.

Conclusions:

• Insulin receptor signaling is essential for maintaining normal heart rate and SAN structure.
• Insulin receptor loss leads to bradycardia and fibrosis through downregulation of HCN4 and HCN1 channels.
• This study reveals a novel role for insulin/IGF-1 signaling in cardiac conduction system physiology.