Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its modulation via phosphorylation.
Adult
Cardiomyopathy, Dilated
/ genetics
Carrier Proteins
/ metabolism
Connectin
/ genetics
Cyclic AMP-Dependent Protein Kinases
/ metabolism
Female
Genetic Predisposition to Disease
Humans
Kinetics
Male
Middle Aged
Mutation
Myocardial Contraction
Myocytes, Cardiac
/ metabolism
Myofibrils
/ metabolism
Phenotype
Phosphoprotein Phosphatases
/ metabolism
Phosphorylation
Troponin I
/ metabolism
Viral Proteins
/ metabolism
Young Adult
Cardiac contractility and energetics
Dilated cardiomyopathy
Length-dependent activation
Super- relaxed state of myosin
Titin
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
07 01 2022
07 01 2022
Historique:
received:
08
11
2019
accepted:
20
10
2020
pubmed:
3
11
2020
medline:
8
3
2022
entrez:
2
11
2020
Statut:
ppublish
Résumé
Dilated cardiomyopathy (DCM) is associated with mutations in many genes encoding sarcomere proteins. Truncating mutations in the titin gene TTN are the most frequent. Proteomic and functional characterizations are required to elucidate the origin of the disease and the pathogenic mechanisms of TTN-truncating variants. We isolated myofibrils from DCM hearts carrying truncating TTN mutations and measured the Ca2+ sensitivity of force and its length dependence. Simultaneous measurement of force and adenosine triphosphate (ATP) consumption in skinned cardiomyocytes was also performed. Phosphorylation levels of troponin I (TnI) and myosin binding protein-C (MyBP-C) were manipulated using protein kinase A and λ phosphatase. mRNA sequencing was employed to overview gene expression profiles. We found that Ca2+ sensitivity of myofibrils carrying TTN mutations was significantly higher than in myofibrils from donor hearts. The length dependence of the Ca2+ sensitivity was absent in DCM myofibrils with TTN-truncating variants. No significant difference was found in the expression level of TTN mRNA between the DCM and donor groups. TTN exon usage and splicing were also similar. However, we identified down-regulation of genes encoding Z-disk proteins, while the atrial-specific regulatory myosin light chain gene, MYL7, was up-regulated in DCM patients with TTN-truncating variants. Titin-truncating mutations lead to decreased length-dependent activation and increased elasticity of myofibrils. Phosphorylation levels of TnI and MyBP-C seen in the left ventricles are essential for the length-dependent changes in Ca2+ sensitivity in healthy donors, but they are reduced in DCM patients with TTN-truncating variants. A decrease in expression of Z-disk proteins may explain the observed decrease in myofibril passive stiffness and length-dependent activation.
Identifiants
pubmed: 33135063
pii: 5949014
doi: 10.1093/cvr/cvaa316
pmc: PMC8752363
doi:
Substances chimiques
Carrier Proteins
0
Connectin
0
TTN protein, human
0
Troponin I
0
Viral Proteins
0
myosin-binding protein C
0
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
PP-lambda protein, Bacteriophage lambda
EC 3.1.3.16
Phosphoprotein Phosphatases
EC 3.1.3.16
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
241-253Subventions
Organisme : British Heart Foundation
ID : PG/17/5/32705
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/11/20/29266
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : P01 HL062426
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.
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