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