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Updated: Aug 9, 2026
In Vitro Assessment of Cardiac Function Using Skinned Cardiomyocytes
Published on: June 22, 2020
Ablation of cardiac myosin-binding protein-C accelerates stretch activation in murine skinned myocardium
Julian E Stelzer1, Sandy B Dunning, Richard L Moss
1Department of Physiology, University of Wisconsin School of Medicine, Madison, WI 53711, USA. stelzer@physiology.wisc.edu
Insights
Cardiac myosin binding protein-C (cMyBP-C) normally limits cardiac muscle stretch activation. Ablation of cMyBP-C accelerates force development and cross-bridge cycling, impacting myocardial function.
Area of Science:
- Cardiovascular Physiology
- Muscle Biology
- Biochemistry
Background:
- Cardiac myosin binding protein-C (cMyBP-C) is a thick filament protein crucial for myocardial function.
- Mutations in the cMyBP-C gene are a frequent cause of hypertrophic cardiomyopathy.
- The precise roles of cMyBP-C in cardiac contraction, particularly stretch activation, remain incompletely understood.
Purpose of the Study:
- To investigate the impact of cMyBP-C on the stretch activation responses in cardiac muscle.
- To elucidate the functional consequences of cMyBP-C deficiency in myocardial contractility.
Main Methods:
- Utilized skinned ventricular preparations from wild-type (WT) and cMyBP-C knockout (cMyBP-C(-/-)) mice.
- Assessed stretch activation responses, including force development and decay kinetics, under varying calcium activations.
- Compared mechanical properties between WT and cMyBP-C deficient myocardium.
Main Results:
- Ablation of cMyBP-C significantly altered stretch activation responses.
- The rates of force decay and delayed force redevelopment were accelerated in cMyBP-C(-/-) myocardium compared to WT.
- These findings suggest cMyBP-C normally constrains myosin cross-bridge interactions with actin.
Conclusions:
- cMyBP-C plays a critical role in regulating the kinetics of cardiac muscle stretch activation.
- Loss of cMyBP-C leads to accelerated cross-bridge cycling and premature force development.
- These alterations may contribute to the pathophysiology of cardiac conditions associated with cMyBP-C dysfunction.
Abstract:
Cardiac myosin binding protein-C (cMyBP-C) is a thick filament accessory protein that binds tightly to myosin, but despite evidence that mutations in the cMyBP-C gene comprise a frequent cause of hypertrophic cardiomyopathy, relatively little is known about the role(s) of cMyBP-C in myocardium. Based on earlier studies demonstrating the potential importance of stretch activation in cardiac contraction, we examined the effects of cMyBP-C on the stretch activation responses of skinned ventricular preparations from wild-type (WT) and homozygous cMyBP-C knockout mice (cMyBP-C(-/-)) previously developed in our laboratory. Sudden stretch of skinned myocardium during maximal or submaximal Ca2+ activations resulted in an instantaneous increase in force that quickly decayed to a minimum and was followed by a delayed redevelopment of force (ie, stretch activation) to levels greater than prestretch force. Ablation of cMyBP-C dramatically altered the stretch activation response, ie, the rates of force decay and delayed force transient were accelerated compared with WT myocardium. These results suggest that cMyBP-C normally constrains the spatial position of myosin cross-bridges, which, in turn, limits both the rate and extent of interaction of cross-bridges with actin. We propose that ablation of cMyBP-C removes this constraint, increases the likelihood of cross-bridge binding to actin, and speeds the rate of delayed force development following stretch. Regardless of the specific mechanism, acceleration of cross-bridge cycling in cMyBP-C(-/-) myocardium could account for the abbreviation of systolic ejection in this mouse as a direct consequence of premature stretch activation of ventricular myocardium.
