Related Experiment Video
Updated: May 11, 2026
Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
Published on: August 1, 2016
Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere
Y Cheng1, X Wan, T A McElfresh
1Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
Insights
Reduced cardiac myosin binding protein C (MyBP-C) expression in mice mimics human hypertrophic cardiomyopathy, causing myofilament dysfunction and electrical abnormalities that may increase arrhythmia risk.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Heart Disease
Background:
- Mutations in cardiac myosin binding protein C (MyBP-C) are a primary genetic cause of familial hypertrophic cardiomyopathy (FHC).
- Most MyBP-C mutations are predicted to decrease MyBP-C expression, but its functional impact on cardiac mechanics and electrophysiology remains unclear.
Purpose of the Study:
- To investigate the functional consequences of reduced MyBP-C expression on myofilament function, calcium (Ca²⁺) handling, and in vivo cardiac performance.
- To model FHC by examining MyBP-C heterozygous null (MyBP-C+/-) mice with MyBP-C expression levels comparable to FHC patients.
Main Methods:
- Utilized MyBP-C+/- mice to assess MyBP-C expression and phosphorylation levels.
- Performed mechanical studies on skinned myocardium to evaluate cross-bridge kinetics and force generation.
- Analyzed intact ventricular myocytes for sarcomere shortening and Ca²⁺ transient dynamics.
- Conducted in vivo assessments including pressure-volume loops and electrocardiograms (ECGs).
Main Results:
- MyBP-C+/- hearts showed reduced MyBP-C expression (32%) and phosphorylation (53%), leading to altered myofilament mechanics including decreased stiffness and accelerated cross-bridge recruitment at low Ca²⁺.
- Intact myocytes exhibited abnormal sarcomere shortening, while Ca²⁺ transient kinetics remained unchanged.
- MyBP-C+/- mice displayed impaired cardiac function (elevated end-diastolic pressure, reduced dP/dt max) and prolonged ECG intervals (QRS, QT), indicating electrical instability.
- Protein kinase A treatment normalized cross-bridge recruitment rates, suggesting a role for phosphorylation in regulating myofilament response.
Conclusions:
- Reduced MyBP-C expression and phosphorylation cause direct myofilament dysfunction, preceding significant Ca²⁺ handling alterations or chamber remodeling in FHC models.
- These myofilament and electrical perturbations contribute to cardiac contractile dysfunction and increase susceptibility to arrhythmias.
- MyBP-C+/- mice serve as a valuable model for studying FHC pathogenesis and potential therapeutic strategies.
Abstract:
Mutations in cardiac myosin binding protein C (MyBP-C) are a common cause of familial hypertrophic cardiomyopathy (FHC). The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca²⁺ homeostasis, and in vivo cardiac function are unknown. To elucidate the effects of decreased MyBP-C expression on cardiac function, we employed MyBP-C heterozygous null (MyBP-C+/-) mice presenting decreases in MyBP-C expression (32%) similar to those of FHC patients carrying MyBP-C mutations. The levels of MyBP-C phosphorylation were reduced 53% in MyBP-C+/- hearts compared with wild-type hearts. Skinned myocardium isolated from MyBP-C+/- hearts displayed decreased cross-bridge stiffness at half-maximal Ca²⁺ activations, increased steady-state force generation, and accelerated rates of cross-bridge recruitment at low Ca²⁺ activations (<15% and <25% of maximum, respectively). Protein kinase A treatment abolished basal differences in rates of cross-bridge recruitment between MyBP-C+/- and wild-type myocardium. Intact ventricular myocytes from MyBP-C+/- hearts displayed abnormal sarcomere shortening but unchanged Ca²⁺ transient kinetics. Despite a lack of left ventricular hypertrophy, MyBP-C+/- hearts exhibited elevated end-diastolic pressure and decreased peak rate of LV pressure rise, which was normalized following dobutamine infusion. Furthermore, electrocardiogram recordings in conscious MyBP-C+/- mice revealed prolonged QRS and QT intervals, which are known risk factors for cardiac arrhythmia. Collectively, our data show that reduced MyBP-C expression and phosphorylation in the sarcomere result in myofilament dysfunction, contributing to contractile dysfunction that precedes compensatory adaptations in Ca²⁺ handling, and chamber remodeling. Perturbations in mechanical and electrical activity in MyBP-C+/- mice could increase their susceptibility to cardiac dysfunction and arrhythmia.
Related Concept Videos
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:08The Sarcomere
Each myosin...
01:16Actin and Myosin in Muscle Contraction
01:26Cross-bridge Cycle
01:25Smooth Muscle Contraction
The onset of contraction is triggered by an increase in calcium ions within the sarcoplasm, similar to the process in striated muscle. However, smooth muscles have a relatively smaller reservoir of the sarcoplasmic...
01:26Imbalances in Cardiac Output
CHF can occur due to the failure of either side of the heart. Left-side failure leads to pulmonary congestion—the right side continues to send blood...