MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM)

Nieves García-Quintáns, Silvia Sacristán, Cristina Márquez-López, Cristina Sánchez-Ramos, Fernando Martinez- de-Benito, David Siniscalco, Andrés González-Guerra, Emilio Camafeita, Marta Roche-Molina, Mariya Lytvyn, David Morera, María I. Guillen, María A. Sanguino, David Sanz-Rosa, Daniel Martín-Pérez, Ricardo Garcia and Juan A. Bernal ()
Additional contact information
Nieves García-Quintáns: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Silvia Sacristán: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Cristina Márquez-López: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Cristina Sánchez-Ramos: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Fernando Martinez- de-Benito: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
David Siniscalco: CSIC
Andrés González-Guerra: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Emilio Camafeita: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Marta Roche-Molina: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Mariya Lytvyn: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
David Morera: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
María I. Guillen: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
María A. Sanguino: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
David Sanz-Rosa: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Daniel Martín-Pérez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Ricardo Garcia: CSIC
Juan A. Bernal: Centro Nacional de Investigaciones Cardiovasculares (CNIC)

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41981-5

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