Constitutive deletion of the obscurin-Ig58/59 domains induces atrial remodeling and Ca2+-based arrhythmogenesis

• DOI: 10.1172/jci.insight.184202
• Publication Date: 2025-01-14T00:11:06Z
• Authors: Alyssa Grogan; Annie Brong; Humberto C. Joca; Liron Boyman; Aaron D. Kaplan; Christopher W. Ward; Maura Greiser; Aikaterini Kontro...

Obscurin is a giant protein that coordinates diverse aspects of striated muscle physiology. immunoglobulin domains 58/59 (Ig58/59) associate with essential sarcomeric and Ca2+ cycling proteins. To explore the pathophysiological significance Ig58/59, we generated Obscn-ΔIg58/59 mouse model, expressing obscurin constitutively lacking Ig58/59. Males in this line develop atrial fibrillation by 6-months, ventricular dilation 12-months. As left ventricles at 6-months exhibit no deficits ultrastructure or signaling, hypothesized susceptibility to arrhythmia may emanate from atria. Ultrastructural evaluation male atria uncovered prominent Z-disk streaming further misalignment Relatedly, isolated cardiomyocytes exhibited increased spark frequency age-specific alterations dynamics, coinciding arrythmia onset progression. Quantitative analysis transverse-axial tubule (TAT) network using super-resolution microscopy demonstrated significant TAT depletion These structural signaling were accompanied expression and/or phosphorylation T-cap, which links transverse-tubules Z-disks, junctophilin-2, connects sarcoplasmic reticulum. Collectively, our work establishes model as reputable genetic for cardiomyopathy provides mechanistic insights into remodeling.