Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects.
Atrial cardiomyocyte
Cardiomyopathy
MYBPHL
MyBP-HL
Myosin binding protein
Ventricular conduction system
Journal
Journal of molecular and cellular cardiology
ISSN: 1095-8584
Titre abrégé: J Mol Cell Cardiol
Pays: England
ID NLM: 0262322
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
18
10
2021
revised:
25
03
2022
accepted:
15
04
2022
pubmed:
10
5
2022
medline:
27
7
2022
entrez:
9
5
2022
Statut:
ppublish
Résumé
A premature truncation of MYBPHL in humans and a loss of Mybphl in mice is associated with dilated cardiomyopathy, atrial and ventricular arrhythmias, and atrial enlargement. MYBPHL encodes myosin binding protein H-like (MyBP-HL). Prior work in mice indirectly identified Mybphl expression in the atria and in small puncta throughout the ventricle. Because of its genetic association with human and mouse cardiac conduction system disease, we evaluated the anatomical localization of MyBP-HL and the consequences of loss of MyBP-HL on conduction system function. Immunofluorescence microscopy of normal adult mouse ventricles identified MyBP-HL-positive ventricular cardiomyocytes that co-localized with the ventricular conduction system marker contactin-2 near the atrioventricular node and in a subset of Purkinje fibers. Mybphl heterozygous ventricles had a marked reduction of MyBP-HL-positive cells compared to controls. Lightsheet microscopy of normal perinatal day 5 mouse hearts showed enrichment of MyBP-HL-positive cells within and immediately adjacent to the contactin-2-positive ventricular conduction system, but this association was not apparent in Mybphl heterozygous hearts. Surface telemetry of Mybphl-null mice revealed atrioventricular block and atrial bigeminy, while intracardiac pacing revealed a shorter atrial relative refractory period and atrial tachycardia. Calcium transient analysis of isolated Mybphl-null atrial cardiomyocytes demonstrated an increased heterogeneity of calcium release and faster rates of calcium release compared to wild type controls. Super-resolution microscopy of Mybphl heterozygous and homozygous null atrial cardiomyocytes showed ryanodine receptor disorganization compared to wild type controls. Abnormal calcium release, shorter atrial refractory period, and atrial dilation seen in Mybphl null, but not wild type control hearts, agree with the observed atrial arrhythmias, bigeminy, and atrial tachycardia, whereas the proximity of MyBP-HL-positive cells with the ventricular conduction system provides insight into how a predominantly atrial expressed gene contributes to ventricular arrhythmias and ventricular dysfunction.
Identifiants
pubmed: 35533732
pii: S0022-2828(22)00077-3
doi: 10.1016/j.yjmcc.2022.04.012
pmc: PMC9329245
mid: NIHMS1806758
pii:
doi:
Substances chimiques
Calcium
SY7Q814VUP
Contactins
0
Cytoskeletal Proteins
0
Myosins
EC 3.6.4.1
Mybphl protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
28-40Subventions
Organisme : NHLBI NIH HHS
ID : F32 HL131304
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL141698
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL141698
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128075
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.
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