{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Grogan A"],"funding":["NIA NIH HHS","NHLBI NIH HHS","NIAMS NIH HHS"],"pagination":["e184202"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11949006"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(4)"],"pubmed_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."],"journal":["JCI insight"],"pubmed_title":["Constitutive deletion of the obscurin-Ig58/59 domains induces atrial remodeling and Ca2+-based arrhythmogenesis."],"pmcid":["PMC11949006"],"funding_grant_id":["K99 HL156005","T32 AR007592","R01 AR077106","P30 AG028747","R01 HL142290"],"pubmed_authors":["Ward CW","Boyman L","Kontrogianni-Konstantopoulos A","Kaplan AD","Greiser M","Brong A","Grogan A","Joca HC"],"additional_accession":[]},"is_claimable":false,"name":"Constitutive deletion of the obscurin-Ig58/59 domains induces atrial remodeling and Ca2+-based arrhythmogenesis.","description":"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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Jan","modification":"2025-07-04T03:05:45.643Z","creation":"2025-07-04T03:05:45.643Z"},"accession":"S-EPMC11949006","cross_references":{"pubmed":["39804820"],"doi":["10.1172/jci.insight.184202"]}}