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

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Abstract

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

Authors

Alyssa Grogan, Annie Brong, Humberto C. Joca, Liron Boyman, Aaron D. Kaplan, Christopher W. Ward, Maura Greiser, Aikaterini Kontrogianni-Konstantopoulos