2026-05-03T05:52:12Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/192552024-09-27T08:54:39Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc García-Quintáns, Nieves author Santiago-Sacristan, Silvia author Márquez-López, Cristina author Sánchez-Ramos, Cristina author Martinez-de-Benito, Fernando author Siniscalco, David author González-Guerra, Andrés author Camafeita, Emilio author Roche-Molina, Marta author Lytvyn, Mariya author Morera, David author Guillen, María I author Sanguino, María A author Sanz-Rosa, David author Martin-Perez, Daniel author Garcia, Ricardo author Bernal, Juan Antonio author 2023-10-13 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. Nat Commun. 2023 Oct 13;14(1):6461. 10.1038/s41467-023-41981-5 2041-1723 Nature communications 37833253 http://hdl.handle.net/20.500.12105/19255 MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM).