MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM)

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...

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Detalles Bibliográficos
Autores: García-Quintáns, N., Sacristán, S., Márquez-López, C., Sánchez-Ramos, Cristina, Martinez-de-Benito, F., Siniscalco, David, González-Guerra, A., Camafeita, E., Roche-Molina, M., Lytvyn, M., Morera, D., Guillen, M.I., Sanguino, M.A., Sanz-Rosa, D., Martín-Pérez, D., García García, Ricardo, Bernal, Juan Antonio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/352750
Acceso en línea:http://hdl.handle.net/10261/352750
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85174275195&doi=10.1038%2fs41467-023-41981-5&partnerID=40&md5=79ea3951b0b9f2271c664e54e0de04ca
Access Level:acceso abierto
Descripción
Sumario: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. © 2023, Springer Nature Limited.

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