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Myocardial dysfunction caused by MyBPC3 P459fs mutation in hypertrophic cardiomyopathy: evidence from multi-omics
Yupeng Wu1,2, Yuzhu Zhang1,3, Qirui Zheng1,3
1Department of Ultrasound, The People's Hospital of China Medical University, The People's Hospital of Liaoning Province, Shenyang, China.
Insights
The MyBPC3 P459fs mutation causes hypertrophic cardiomyopathy (HCM) by impairing myocardial function and fiber formation. This study reveals underlying pathways, aiding potential treatments for HCM patients.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Cellular Biology
Background:
- Mutations in sarcomere protein genes, especially MYBPC3, are primary causes of hypertrophic cardiomyopathy (HCM).
- The pathogenic MYBPC3 P459fs mutation is identified in HCM patients, but its structure-function relationships and underlying pathways remain unclear.
- Understanding these molecular mechanisms is crucial for developing targeted therapies for HCM.
Purpose of the Study:
- To investigate the cellular and molecular effects of the MYBPC3 P459fs mutation in hypertrophic cardiomyopathy (HCM).
- To explore the structure-function relationship and potential pathogenic pathways associated with this specific mutation.
- To provide insights into the pathogenesis of HCM and identify potential therapeutic targets.
Main Methods:
- Employed multi-omics approaches (metabolomics, proteomics) and super-resolution imaging.
- Assessed myocardial function in HCM patients with MYBPC3 P459fs mutation (MyBPC3-P459fs HCMs) versus healthy controls (HCs) using echocardiography.
- Analyzed H9C2 myocardial cells with MYBPC3 P459fs mutation (P459fs cells) versus wild type (WT cells) for fiber formation and pathway alterations.
Main Results:
- Echocardiography revealed left ventricular diastolic and systolic dysfunction in MyBPC3-P459fs HCMs.
- Super-resolution imaging showed reduced and shorter myocardial fiber formation in P459fs cells compared to WT cells.
- Multi-omics data indicated significant alterations in mitochondrial integrity, energy metabolism, oxidative stress, inflammation, and actin binding due to the P459fs mutation.
Conclusions:
- The MYBPC3 P459fs mutation leads to myocardial dysfunction and fiber disarray in HCM.
- Identified potential molecular pathways contributing to HCM pathogenesis linked to this mutation.
- Findings offer a basis for understanding structural and functional deficits in MYBPC3-P459fs mutation-associated HCM and may inform future treatments.
Introduction:
Mutations in the sarcomere protein, particularly in cardiac myosin binding protein C gene (MyBPC3), were the most frequent genetic cause of hypertrophic cardiomyopathy (HCM). The pathogenic MyBPC3 P459fs mutation has been reported in HCM patients. However, there was limited knowledge of the structure-function relationships and potential pathways in clinical HCM with MyBPC3 P459fs mutation.
Methods:
We used multi-omics approaches and super-resolution imaging to explore the effects of MyBPC3 P459fs mutation on humans and cells. HCM patients carrying MyBPC3 P459fs mutation (MyBPC3-P459fs HCMs) and healthy controls (HCs) were evaluated for myocardial function using both conventional and advanced echocardiography. In parallel, H9C2 myocardial cells infected with either MyBPC3 P459fs mutation (P459fs cells) or its wild type (WT cells) were investigated for myocardial fiber formation and the potential pathways behind this using super-resolution imaging and metabolomics and proteomics.
Results:
First, conventional and advanced echocardiography showed that MyBPC3-P459fs HCMs exhibited left ventricular diastolic and systolic dysfunction. Subsequently, super-resolution imaging indicated that P459fs cells formed fewer and shorter myocardial fibers in the cytoplasm compared to WT cells. Moreover, our metabolomic and proteomic data suggested several key components of mitochondrial membrane integrity, myocardial remodeling, myocardial energy metabolism, oxidative stress, inflammation, and actin binding capacity were significantly altered in response to P459fs mutation.
Conclusions:
This investigation indicated myocardial dysfunction and myocardial fiber disarray in clinical HCMs with MyBPC3 P459fs mutation and added potential pathways underlying this. These findings provided a link between the observed structural and functional disorders in MyBPC3 P459fs mutation and its onset of HCM pathogenesis and might have a significant translational contribution to effective treatment in HCM patients with MyBPC3 P459fs mutation.
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