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Published on: August 8, 2022
Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic
David Barefield1, Mohit Kumar, Pieter P de Tombe
1Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, Illinois.
Insights
Even without symptoms, carriers of MYBPC3 mutations show early cardiac dysfunction. This study reveals subtle impairments in heterozygous mice, suggesting potential for hypertrophic cardiomyopathy (HCM) development.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Heart Disease
Background:
- Hypertrophic cardiomyopathy (HCM) is often caused by mutations in sarcomere protein genes, particularly MYBPC3.
- MYBPC3 mutations, especially truncations, are common in HCM and can lead to undetectable protein levels.
- Heterozygous carriers of MYBPC3 mutations display variable disease penetrance and late-onset symptoms.
Purpose of the Study:
- To investigate subtle functional impairments in heterozygous MYBPC3 mutation carriers before overt HCM development.
- To compare functional alterations at the whole-heart and single-cell levels in MYBPC3 knock-in mice versus wild-type littermates.
- To identify early signs of cardiac dysfunction in asymptomatic carriers.
Main Methods:
- Utilized heterozygous (+/t) knock-in MYBPC3 truncation mutation mice and wild-type (+/+) littermates for comparison.
- Assessed cardiac function at the single-cell level by measuring maximal force development at specific sarcomere lengths.
- Evaluated in vivo cardiac function using echocardiography to determine early/after (E/A) and E'/A' ratios for diastolic function assessment.
Main Results:
- MYBPC3 transcription was reduced by approximately 40% in +/t mice, with no changes in protein levels, phosphorylation, or cardiac morphology.
- Significantly decreased maximal force development was observed in +/t mice at sarcomere lengths of 1.9 μm and 2.3 μm.
- Heterozygous mice exhibited reduced in vivo E/A and E'/A ratios, indicating diastolic dysfunction.
Conclusions:
- Seemingly asymptomatic heterozygous MYBPC3 mutation carriers experience functional cardiac impairments.
- These subtle functional deficits, including reduced force generation and diastolic dysfunction, may precede the clinical manifestation of HCM.
- The findings highlight the importance of early detection and monitoring in carriers of MYBPC3 mutations.
Abstract:
The etiology of hypertrophic cardiomyopathy (HCM) has been ascribed to mutations in genes encoding sarcomere proteins. In particular, mutations in MYBPC3, a gene which encodes cardiac myosin binding protein-C (cMyBP-C), have been implicated in over one third of HCM cases. Of these mutations, 70% are predicted to result in C'-truncated protein products, which are undetectable in tissue samples. Heterozygous carriers of these truncation mutations exhibit varying penetrance of HCM, with symptoms often occurring later in life. We hypothesize that heterozygous carriers of MYBPC3 mutations, while seemingly asymptomatic, have subtle functional impairments that precede the development of overt HCM. This study compared heterozygous (+/t) knock-in MYBPC3 truncation mutation mice with wild-type (+/+) littermates to determine whether functional alterations occur at the whole-heart or single-cell level before the onset of hypertrophy. The +/t mice show ∼40% reduction in MYBPC3 transcription, but no changes in cMyBP-C level, phosphorylation status, or cardiac morphology. Nonetheless, +/t mice show significantly decreased maximal force development at sarcomere lengths of 1.9 μm (+/t 68.5 ± 4.1 mN/mm(2) vs. +/+ 82.2 ± 3.2) and 2.3 μm (+/t 79.2 ± 3.1 mN/mm(2) vs. +/+ 95.5 ± 2.4). In addition, heterozygous mice show significant reductions in vivo in the early/after (E/A) (+/t 1.74 ± 0.12 vs. +/+ 2.58 ± 0.43) and E'/A' (+/t 1.18 ± 0.05 vs. +/+ 1.52 ± 0.15) ratios, indicating diastolic dysfunction. These results suggest that seemingly asymptomatic heterozygous MYBPC3 carriers do suffer impairments that may presage the onset of HCM.
