Dataset Information

Proteomic analysis of left ventricles containing the obscurin R4344Q mutation linked to hypertrophic cardiomyopathy and myocardia containing obscurin lacking Immunoglobulin domains 58/59 (Ig58/59)

ABSTRACT: Cardiac lysates prepared from left ventricles of 1-year-old female wild-type mice, mice carrying the obscurin R4344Q mutation, and mice carrying obscurin lacking the Ig58/59 domains (ΔIg58/59) were subjected to isobaric tandem-mass tagging, liquid chromatography, and mass spectrometry.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Li-Yen Hu

LAB HEAD: Aikaterini Kontrogianni-Konstantopoulos

PROVIDER: PXD017314 | Pride | 2020-06-18

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	TB-CS-160801_KonstantopoulosA_LH_TMT_Exp2_bRP24fr_PhosST_FixedNtermTMTMethyltio_F.msf	Msf
	TB-CS-160801_KonstantopoulosA_LH_TMT_Exp2_bRP_1.raw	Raw
	TB-CS-160801_KonstantopoulosA_LH_TMT_Exp2_bRP_10.raw	Raw
	TB-CS-160801_KonstantopoulosA_LH_TMT_Exp2_bRP_11.raw	Raw
	TB-CS-160801_KonstantopoulosA_LH_TMT_Exp2_bRP_12.raw	Raw

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Publications

Proteomic Analysis of Myocardia Containing the Obscurin R4344Q Mutation Linked to Hypertrophic Cardiomyopathy.

Hu Li-Yen R LR Kontrogianni-Konstantopoulos Aikaterini A

Frontiers in physiology 20200518

Obscurin is a giant cytoskeletal protein with structural and regulatory roles encoded by the <i>OBSCN</i> gene. Recently, mutations in <i>OBSCN</i> were associated with the development of different forms of cardiomyopathies, including hypertrophic cardiomyopathy (HCM). We previously reported that homozygous mice carrying the HCM-linked R4344Q obscurin mutation develop arrhythmia by 1-year of age under sedentary conditions characterized by increased heart rate, frequent incidents of premature ven ...[more]

PMID: 32528308

Similar Datasets

Project 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.