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American Heart Association

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Final ID: Or105

Constitutive Deletion of the Obscurin Ig58/59 Domains Induces Structural and Electrophysiological Remodeling in Atria

Abstract Body: Introduction
Obscurin is a giant cytoskeletal protein that supports muscle development, tethers intracellular compartments and regulates contraction. In the ObscnΔIg58/59 mouse model, expressing obscurin lacking Immunoglobulin (Ig) domains 58 and 59, aging males exhibit irregular heart rhythm with prominent atrial fibrillation, atrial enlargement, and progressive remodeling of the ventricles. A mechanistic basis for the emergence of arrhythmia early on could not be identified in ObscnΔIg58/59 ventricles, suggesting that the atria are preferentially impacted by deletion of the obscurin Ig58/59 module prior to the ventricles.
Hypothesis
We hypothesize that Ig58/59 deletion elicits unique structural, electrical, and functional consequences in the atria preceding ventricular maladaptation.
Aims
I. Examine the structural organization of ObscnΔIg58/59 atria
II. Assess Ca2+ handling in isolated atrial cardiomyocytes and determine molecular alterations.
Methods
Electron microscopy and super resolution microscopy were utilized to visualize sarcomeric ultrastructure and the transverse-axial tubule (TAT) network, respectively. Ca2+ handling activity and synchrony were also resolved, while Phos-Tag gels were used to quantify T-cap phospho-species.
Results
ObscnΔIg58/59 atria exhibited misalignment of Z-disks. Spontaneous and stimulated Ca2+ cycling behavior were [AB1] differentially disrupted in atrial cardiomyocytes in 6- and 12-month ObscnΔIg58/59 males. Relatedly, atrial cells showed an age-dependent deterioration in TAT architecture. Finally, as a function of aging, ObscnΔIg58/59 atria displayed alterations in the expression and phosphorylation of T-cap, a Z-disk protein implicated in the integration of t-tubules with the sarcomeric cytoskeleton.
Conclusions
The structural and electrical alterations that arise in ObscnΔIg58/59 atria precede ventricular dysfunction and coincide with the emergence of atrial fibrillation. Collectively, our work indicates that the atria are principally affected by Ig58/59 elimination, instigating arrhythmias and morphological alterations with age. The ObscnΔIg58/59 mouse model has thus emerged as a proxy for atrial cardiomyopathy.
  • Brong, Annie  ( University of Maryland, Baltimore , Baltimore , Maryland , United States )
  • Grogan, Alyssa  ( Duke University , Durham , North Carolina , United States )
  • Cavalcante Joca, Humberto  ( University of Maryland Baltimore , Baltimore , Maryland , United States )
  • Boyman, Liron  ( University of Maryland Baltimore , Baltimore , Maryland , United States )
  • Kaplan, Aaron  ( University of Maryland Baltimore , Baltimore , Maryland , United States )
  • Ward, Christopher  ( UM-Orthopedics , Baltimore , Maryland , United States )
  • Greiser, Maura  ( University of Maryland Baltimore , Baltimore , Maryland , United States )
  • Kontrogianni-konstantopoulos, Aikaterini  ( University of Maryland, Baltimore , Baltimore , Maryland , United States )
  • Author Disclosures:
    Annie Brong: DO NOT have relevant financial relationships | Alyssa Grogan: DO NOT have relevant financial relationships | Humberto Cavalcante Joca: DO NOT have relevant financial relationships | Liron Boyman: No Answer | Aaron Kaplan: DO NOT have relevant financial relationships | Christopher Ward: DO NOT have relevant financial relationships | Maura Greiser: No Answer | Aikaterini Kontrogianni-Konstantopoulos: DO NOT have relevant financial relationships
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Early Career Pre-Conference Session 1: Next Best Thing

Monday, 07/22/2024 , 09:15AM - 10:15AM

Early Career Session

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