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

## TL;DR

Deleting specific parts of a giant muscle protein in mice causes heart rhythm issues and heart structure changes, offering a new model to study heart disease.

## Contribution

A novel mouse model with constitutive deletion of obscurin-Ig58/59 domains is introduced for studying atrial cardiomyopathy and arrhythmia mechanisms.

## Key findings

- Mice lacking obscurin-Ig58/59 domains develop atrial fibrillation and heart dilation with age.
- Atrial cardiomyocytes show increased calcium signaling and structural changes in transverse tubules.
- Altered expression of proteins linking calcium channels to heart muscle structures is observed.

## 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.

Our genetic murine model (Obscn-ΔIg58/59) reliably recapituales the hallmarks of atrial cardiomyopathy and can be used as a reputable proxy to study disease pathogenicity, which remains largely unknown.