MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM).
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 10 2023
13 10 2023
Historique:
received:
02
03
2023
accepted:
26
09
2023
medline:
23
10
2023
pubmed:
14
10
2023
entrez:
13
10
2023
Statut:
epublish
Résumé
The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT-deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy.
Identifiants
pubmed: 37833253
doi: 10.1038/s41467-023-41981-5
pii: 10.1038/s41467-023-41981-5
pmc: PMC10575922
doi:
Substances chimiques
Actomyosin
9013-26-7
Plakophilins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6461Informations de copyright
© 2023. Springer Nature Limited.
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