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Updated: Aug 7, 2025
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Cardiomyocyte Apoptosis Is Associated with Contractile Dysfunction in Stem Cell Model of MYH7 E848G Hypertrophic
Alexander M Loiben1,2,3, Wei-Ming Chien1,2,3,4, Clayton E Friedman1,2,3
1Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA.
Insights
Missense mutations in MYH7 cause hypertrophic cardiomyopathy (HCM). This study found MYH7-E848G variant increases cell size and apoptosis, but this cell death is independent of p53, suggesting new therapeutic targets for HCM.
Area of Science:
- Cardiovascular Biology
- Genetics
- Stem Cell Biology
Background:
- Missense mutations in myosin heavy chain 7 (MYH7) are a primary genetic cause of hypertrophic cardiomyopathy (HCM).
- The precise molecular mechanisms driving MYH7-associated HCM, particularly concerning cellular dysfunction and death, remain incompletely understood.
- Understanding these mechanisms is crucial for developing targeted therapies for HCM patients.
Purpose of the Study:
- To investigate the cellular and molecular consequences of the pathogenic MYH7 E848G missense variant in human cardiomyocytes.
- To determine the role of p53 signaling in the observed cardiomyocyte dysfunction and apoptosis associated with the MYH7 E848G variant.
- To explore potential therapeutic strategies targeting cell death pathways in MYH7-based HCM.
Main Methods:
- Generation of isogenic human induced pluripotent stem cells (hiPSCs) carrying the heterozygous MYH7 E848G variant.
- Assessment of cardiomyocyte size, contractility (twitch force) in engineered heart tissue (EHT), and apoptosis.
- Genetic ablation of the TP53 gene to evaluate the role of p53 in MYH7 E848G-induced phenotypes.
Main Results:
- MYH7 E848G cardiomyocytes exhibited increased cell size and reduced EHT twitch force, mirroring clinical systolic dysfunction in HCM patients.
- Increased cardiomyocyte apoptosis was observed in MYH7 E848G models, correlating with elevated p53 activity.
- Genetic inactivation of TP53 failed to rescue cardiomyocyte survival or restore EHT contractility, demonstrating p53-independent mechanisms.
Conclusions:
- The MYH7 E848G variant induces cardiomyocyte apoptosis and contractile dysfunction through p53-independent pathways.
- These findings highlight cardiomyocyte apoptosis as a key feature of the MYH7 E848G HCM phenotype in vitro.
- Targeting p53-independent cell death pathways presents a promising avenue for therapeutic intervention in HCM patients with systolic dysfunction.
Abstract:
Missense mutations in myosin heavy chain 7 (MYH7) are a common cause of hypertrophic cardiomyopathy (HCM), but the molecular mechanisms underlying MYH7-based HCM remain unclear. In this work, we generated cardiomyocytes derived from isogenic human induced pluripotent stem cells to model the heterozygous pathogenic MYH7 missense variant, E848G, which is associated with left ventricular hypertrophy and adult-onset systolic dysfunction. MYH7E848G/+ increased cardiomyocyte size and reduced the maximum twitch forces of engineered heart tissue, consistent with the systolic dysfunction in MYH7E848G/+ HCM patients. Interestingly, MYH7E848G/+ cardiomyocytes more frequently underwent apoptosis that was associated with increased p53 activity relative to controls. However, genetic ablation of TP53 did not rescue cardiomyocyte survival or restore engineered heart tissue twitch force, indicating MYH7E848G/+ cardiomyocyte apoptosis and contractile dysfunction are p53-independent. Overall, our findings suggest that cardiomyocyte apoptosis is associated with the MYH7E848G/+ HCM phenotype in vitro and that future efforts to target p53-independent cell death pathways may be beneficial for the treatment of HCM patients with systolic dysfunction.
