PXD028904-1

PXD028904 is an original dataset announced via ProteomeXchange.

Title	New molecular insights into atrial fibrillation due to obscurin Ig58/59 deletion
Description	Obscurins are giant, modular, cytoskeletal proteins that regulate striated muscle structure and function. Immunoglobulin domains 58/59 (Ig58/59) of obscurin interact with diverse proteins including titin variants and phospholamban. Mutations within Ig58/59 that alter these binding interactions have been linked to the development of myopathy in humans, underscoring the pathophysiological significance of this module. We previously generated a constitutive deletion mouse model, Obscn-ΔIg58/59, that expresses obscurin lacking Ig58/59 and comprehensively characterized the effects of this deletion on cardiac morphology and function through aging. Our findings demonstrated that Obscn-ΔIg58/59 male animals develop severe arrhythmia characterized by spontaneous atrial fibrillation/junctional escape by 6-months of age, with atrial enlargement and ventricular remodeling manifesting by 12-months. Herein, we aim to mechanistically evaluate the impact of the Ig58/59 deletion in atria at the cellular level and determine the molecular basis for atrial enlargement and arrhythmia due to the physiological process of aging. Ultrastructural evaluation of sedentary aging male Obscn-ΔIg58/59 atria revealed prominent Z-disk streaming and misalignment. More importantly, Obscn-ΔIg58/59 atrial cardiomyocytes exhibited increased Ca2+ spark frequency and age-specific alterations in Ca2+ cycling kinetics and sarcoplasmic reticulum Ca2+ content that preceded those observed in Obscn-ΔIg58/59 ventricular cardiomyocytes. Proteomic and phospho-proteomic analyses revealed extensive and novel alterations in the expression and phosphorylation profile of major cytoskeletal proteins, Ca2+ regulators, and Z-disk associated protein complexes in Obscn-ΔIg58/59 atria through aging that likely underlie the observed atrial pathologies. These studies are the first to evaluate the role of obscurin in atria and to reveal chamber-specific molecular alterations due to Ig58/59 deletion. Moreover, our findings provide new molecular insights into a genetic model of spontaneous atrial fibrillation and remodeling where atrial dysfunction precedes ventricular maladaptation.
HostingRepository	PRIDE
AnnounceDate	2023-04-11
AnnouncementXML	Submission_2023-04-11_05:36:46.304.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	WeiliangHuang
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-10-04 04:44:58	ID requested
⏵ 1	2023-04-11 05:36:46	announced
2	2023-11-14 09:01:15	announced	2023-11-14: Updated project metadata.

submitter keyword: arrhythmia, Z-disk, Ca2+ cycling,obscurin, atrial fibrillation

MaureenKane
contact affiliation	University of Maryland, Baltimore
contact email	mkane@rx.umaryland.edu
lab head
WeiliangHuang
contact affiliation	University of Maryland, Baltimore
contact email	whuang@rx.umaryland.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD028904
     1. Label: PRIDE project
     2. Name: New molecular insights into atrial fibrillation due to obscurin Ig58/59 deletion