Key result
The cMyBP-C mutations D75N and P161S disrupt calcium regulation of contractile force and affect the kinetics of its development in isolated slow skeletal muscle fibers.
Why the study?
Mutations in cMyBP-C lead to hypercontractility and myocardial hypertrophy, but the effects of the hypertrophic cardiomyopathy-related D75N and P161S mutations on the mechanism of force generation required investigation.
The D75N and P161S mutations in cMyBP-C disrupt calcium regulation and contractile force kinetics, providing a mechanistic basis for impaired cardiac diastolic function and myocardial hypertrophy.
Caution against clinical translation; hypothesis-generating for cMyBP-C mutation effects on contractility.
The cardiac myosin binding protein-C (cMyBP-C) regulates cross-bridge formation and controls the duration of systole and diastole at the whole heart level. As known, mutations in cMyBP-C increase the cross-bridge number and rate of their cycling, hypercontractility, and myocardial hypertrophy. We investigated the effects of the mutations D75N and P161S of cMyBP-C related to hypertrophic cardiomyopathy on the mechanism of force generation in isolated slow skeletal muscle fibers. The mutation D75N slowed the kinetics of force development but did not affect the relaxation rate. The mutation P161S slowed both the relaxation and force development. The mutation D75N increased the calcium sensitivity of force, and the mutation P161S decreased it. The mutation D75N decreased the maximal isometric tension and increased the tension and stiffness at low calcium. Both mutations studied disrupt the calcium regulation of contractile force and affect the kinetics of its development and thus may impair cardiac diastolic function and cause myocardial hypertrophy.
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Nabiev et al. (2024) studied Hypertrophic cardiomyopathy. Mutations D75N and P161S of cMyBP-C was evaluated on Force generation, calcium regulation, and kinetics of muscle contraction. The cMyBP-C mutations D75N and P161S disrupt calcium regulation of contractile force and affect the kinetics of its development in isolated slow skeletal muscle fibers.
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