García Quintáns, NievesSacristán, SilviaMárquez López, CristinaSánchez Ramos, CristinaMartínez de Benito, FernandoSiniscalco, DavidGonzález Guerra, AndrésCamafeita, EmilioSanz Rosa, DavidBernal, Juan AntonioEt al.2023-11-022023-11-022023García-Quintáns, N., Sacristán, S., Márquez-López, C., Sánchez-Ramos, C., Martínez-de-Benito, F., Siniscalco, D., González-Guerra, A., Camafeita, E., Roche-Molina, M., Lytvyn, M., Morera, D., Guillén, M. I., Sanguino, M. A., Sanz-Rosa, D., Martín-Pérez, D., García, R., & Bernal, J. A. (2023). MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (Acm). Nature Communications, 14(1), 6461. https://doi.org/10.1038/s41467-023-41981-52041-1723http://hdl.handle.net/11268/12330The 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.engAttribution 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Cardiomiopatíasjournal article10.1038/s41467-023-41981-5open accessEnfermedad cardiovascularMedicina preventivaGenética humana