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

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

doi:10.1172/jci.insight.184202

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

Alyssa Grogan,¹ Annie Brong,¹ Humberto C. Joca,² Liron Boyman,³ Aaron D. Kaplan,³ Christopher W. Ward,² Maura Greiser,³ and Aikaterini Kontrogianni-Konstantopoulos¹

Published January 13, 2025 - More info

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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 arrythmia 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 and/or phosphorylation of T-cap, 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.

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

Alyssa Grogan,¹ Annie Brong,¹ Humberto C. Joca,² Liron Boyman,³ Aaron D. Kaplan,³ Christopher W. Ward,² Maura Greiser,³ and Aikaterini Kontrogianni-Konstantopoulos¹

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

Alyssa Grogan,1 Annie Brong,1 Humberto C. Joca,2 Liron Boyman,3 Aaron D. Kaplan,3 Christopher W. Ward,2 Maura Greiser,3 and Aikaterini Kontrogianni-Konstantopoulos1

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Alyssa Grogan,¹ Annie Brong,¹ Humberto C. Joca,² Liron Boyman,³ Aaron D. Kaplan,³ Christopher W. Ward,² Maura Greiser,³ and Aikaterini Kontrogianni-Konstantopoulos¹