Nabiev Salavat R, Kopylova Galina V, Nefedova Victoria V, Matyushenko Alexander M, Shchepkin Daniil V, Bershitsky Sergey Y
Institute of Immunology and Physiology, Russian Academy of Sciences, 620049 Yekaterinburg, Russia.
Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia.
Int J Mol Sci. 2024 Dec 13;25(24):13405. doi: 10.3390/ijms252413405.
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.
心肌肌球蛋白结合蛋白C（cMyBP-C）调节横桥形成，并在全心水平控制收缩期和舒张期的持续时间。众所周知，cMyBP-C中的突变会增加横桥数量及其循环速率、导致心肌过度收缩和心肌肥大。我们研究了与肥厚型心肌病相关的cMyBP-C的D75N和P161S突变对离体慢肌纤维中力产生机制的影响。D75N突变减慢了力产生的动力学，但不影响松弛速率。P161S突变同时减慢了松弛和力产生的速度。D75N突变增加了力的钙敏感性，而P161S突变降低了钙敏感性。D75N突变降低了最大等长张力，并增加了低钙状态下的张力和刚度。所研究的这两种突变均破坏了收缩力的钙调节，并影响其产生的动力学，因此可能损害心脏舒张功能并导致心肌肥大。
