Related Experiment Video
Updated: May 23, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in
Bodvaël Fraysse1, Florian Weinberger, Sonya C Bardswell
1INSERM U974, Institut de Myologie, Paris, France.
Insights
Hypertrophic cardiomyopathy (HCM) is linked to MYBPC3 mutations. This study shows increased myofilament Ca(2+) sensitivity and diastolic dysfunction precede left ventricular hypertrophy (LVH) in a new mouse model.
Area of Science:
- Cardiovascular Biology
- Genetics
- Molecular Medicine
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease often caused by mutations in the MYBPC3 gene.
- The precise mechanisms linking MYBPC3 mutations to the HCM phenotype are not fully understood.
- Existing mouse models have limitations in reflecting human HCM, complicating the study of early functional changes.
Purpose of the Study:
- To investigate if myofilament calcium (Ca2+) sensitization and diastolic dysfunction occur before or alongside left ventricular hypertrophy (LVH) in HCM.
- To utilize a novel Mybpc3-targeted knock-in mouse model that accurately mimics human HCM.
Main Methods:
- Functional assessment of cardiac myocytes (skinned and intact) and whole hearts in wild-type and Mybpc3 knock-in mice.
- Echocardiography and Doppler analysis to evaluate cardiac structure and function.
- Comparison between homozygous and heterozygous knock-in mice to differentiate effects.
Main Results:
- Homozygous knock-in mice showed increased myofilament Ca2+ sensitivity, faster Ca2+ transient decay, LVH, and both systolic and diastolic dysfunction.
- Heterozygous knock-in mice (modeling human HCM) exhibited increased myofilament Ca2+ sensitivity, faster Ca2+ transient decay, and diastolic dysfunction, but no LVH or systolic dysfunction.
- These early changes were independent of LVH, suggesting compensatory mechanisms for relaxation.
Conclusions:
- Myofilament Ca2+ sensitization and diastolic dysfunction are early consequences of MYBPC3 mutations in HCM, preceding LVH.
- Accelerated Ca2+ transients may represent a compensatory response to normalize relaxation.
- This HCM mouse model is valuable for studying diastolic heart failure mechanisms and potential therapies.
Abstract:
Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C). The mechanisms leading from gene mutations to the HCM phenotype remain incompletely understood, partially because current mouse models of HCM do not faithfully reflect the human situation and early hypertrophy confounds the interpretation of functional alterations. The goal of this study was to evaluate whether myofilament Ca(2+) sensitization and diastolic dysfunction are associated or precede the development of left ventricular hypertrophy (LVH) in HCM. We evaluated the function of skinned and intact cardiac myocytes, as well as the intact heart in a recently developed Mybpc3-targeted knock-in mouse model carrying a point mutation frequently associated with HCM. Compared to wild-type, 10-week old homozygous knock-in mice exhibited i) higher myofilament Ca(2+) sensitivity in skinned ventricular trabeculae, ii) lower diastolic sarcomere length, and faster Ca(2+) transient decay in intact myocytes, and iii) LVH, reduced fractional shortening, lower E/A and E'/A', and higher E/E' ratios by echocardiography and Doppler analysis, suggesting systolic and diastolic dysfunction. In contrast, heterozygous knock-in mice, which mimic the human HCM situation, did not exhibit LVH or systolic dysfunction, but exhibited higher myofilament Ca(2+) sensitivity, faster Ca(2+) transient decay, and diastolic dysfunction. These data demonstrate that myofilament Ca(2+) sensitization and diastolic dysfunction are early phenotypic consequences of Mybpc3 mutations independent of LVH. The accelerated Ca(2+) transients point to compensatory mechanisms directed towards normalization of relaxation. We propose that HCM is a model for diastolic heart failure and this mouse model could be valuable in studying mechanisms and treatment modalities.
