MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM).
Nieves García-QuintánsSilvia SacristánCristina Márquez-LópezCristina Sánchez-RamosFernando Martínez de BenitoDavid SiniscalcoAndrés Gonzalez-GuerraEmilio CamafeitaMarta Roche-MolinaMariya LytvynDavid MoreraMaría I GuillenMaría A SanguinoDavid Sanz-RosaDaniel Martín-PérezRicardo GarciaJuan Antonio BernalPublished in: Nature communications (2023)
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.
Keyphrases
- hypertrophic cardiomyopathy
- left ventricular
- heart failure
- poor prognosis
- blood pressure
- computed tomography
- wild type
- binding protein
- skeletal muscle
- smooth muscle
- mouse model
- contrast enhanced
- copy number
- pulmonary hypertension
- protein protein
- induced apoptosis
- magnetic resonance imaging
- small molecule
- stem cells
- dual energy
- atrial fibrillation
- magnetic resonance
- signaling pathway
- cell therapy
- long non coding rna
- genome wide
- cell cycle arrest
- pulmonary artery
- protein kinase
- pulmonary arterial hypertension