Cooperative mechanisms underlie differences in myocardial contractile dynamics between large and small mammals.

IF 3.3 2区 医学 Q1 PHYSIOLOGY
Journal of General Physiology Pub Date : 2023-11-06 Epub Date: 2023-09-19 DOI:10.1085/jgp.202213315
Jitandrakumar R Patel, Kayla J V Park, Aidan S Bradshaw, Tuan Phan, Daniel P Fitzsimons
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引用次数: 0

Abstract

Ca2+ binding to troponin C (TnC) and myosin cross-bridge binding to actin act in a synergistic cooperative manner to modulate myocardial contraction and relaxation. The responsiveness of the myocardial thin filament to the activating effects of Ca2+ and myosin cross-bridge binding has been well-characterized in small mammals (e.g., mice). Given the nearly 10-fold difference in resting heart rates and twitch kinetics between small and large mammals, it is unlikely that the cooperative mechanisms underlying thin filament activation are identical in these two species. To test this idea, we measured the Ca2+ dependencies of steady-state force and the rate constant of force redevelopment (ktr) in murine and porcine permeabilized ventricular myocardium. While murine myocardium exhibited a steep activation-dependence of ktr, the activation-dependent profile of ktr was significantly reduced in porcine ventricular myocardium. Further insight was attained by examining force-pCa and ktr-pCa relationships. In the murine myocardium, the pCa50 for ktr was right-shifted compared with the pCa50 for force, meaning that increases in steady-state force occurred well before increases in the rate of force redevelopment were observed. In the porcine myocardium, we observed a tighter coupling of the force-pCa and ktr-pCa relationships, as evidenced by near-maximal rates of force redevelopment at low levels of Ca2+ activation. These results demonstrate that the molecular mechanisms underlying the cooperative activation of force are a dynamic property of the mammalian heart, involving, at least in part, the species- and tissue-specific expression of cardiac myosin heavy chain isoforms.

协作机制是大型和小型哺乳动物心肌收缩动力学差异的基础。
Ca2+与肌钙蛋白C(TnC)的结合和肌球蛋白与肌动蛋白的跨桥结合以协同合作的方式调节心肌收缩和舒张。心肌细丝对Ca2+和肌球蛋白跨桥结合的激活作用的反应性在小型哺乳动物(例如小鼠)中已经得到了很好的表征。考虑到小型和大型哺乳动物在静息心率和抽搐动力学方面存在近10倍的差异,这两个物种细丝激活的协同机制不太可能相同。为了验证这一观点,我们测量了小鼠和猪透化心室心肌中稳态力的Ca2+依赖性和力再开发速率常数(ktr)。虽然小鼠心肌表现出强烈的ktr激活依赖性,但在猪心室心肌中,ktr的激活依赖性显著降低。通过检查力pCa和ktr-pCa的关系获得了进一步的见解。在小鼠心肌中,与力的pCa50相比,ktr的pCa50发生了右移,这意味着稳态力的增加早在观察到力再发展速率的增加之前就发生了。在猪心肌中,我们观察到力pCa和ktr-pCa关系的更紧密耦合,如在低Ca2+激活水平下接近最大的力再开发率所证明的。这些结果表明,协同激活力的分子机制是哺乳动物心脏的一种动态特性,至少部分涉及心肌肌球蛋白重链亚型的物种和组织特异性表达。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.00
自引率
10.50%
发文量
88
审稿时长
6-12 weeks
期刊介绍: General physiology is the study of biological mechanisms through analytical investigations, which decipher the molecular and cellular mechanisms underlying biological function at all levels of organization. The mission of Journal of General Physiology (JGP) is to publish mechanistic and quantitative molecular and cellular physiology of the highest quality, to provide a best-in-class author experience, and to nurture future generations of independent researchers. The major emphasis is on physiological problems at the cellular and molecular level.
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