Modeling the effects of thin filament near-neighbor cooperative interactions in mammalian myocardium.

IF 3.3 2区 医学 Q1 PHYSIOLOGY
Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-01-27 DOI:10.1085/jgp.202413582
Tuan A Phan, Daniel P Fitzsimons
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引用次数: 0

Abstract

The mechanisms underlying cooperative activation and inactivation of myocardial force extend from local, near-neighbor interactions involving troponin-tropomyosin regulatory units (RU) and crossbridges (XB) to more global interactions across the sarcomere. To better understand these mechanisms in the hearts of small and large mammals, we undertook a simplified mathematical approach to assess the contribution of three types of near-neighbor cooperative interactions, i.e., RU-induced, RU-activation (RU-RU), crossbridge-induced, crossbridge-binding (XB-XB), and XB-induced, RU-activation (XB-RU). We measured the Ca2+ and activation dependence of the rate constant of force redevelopment in murine- and porcine-permeabilized ventricular myocardium. Mathematical modeling of these three near-neighbor interactions yielded nonlinear expressions for the RU-RU and XB-RU rate coefficients (kon and koff) and XB-XB rate coefficients describing the attachment of force-generating crossbridges (f and f'). The derivation of single cooperative coefficient parameters (u = RU-RU, w = XB-RU, and v = XB-XB) permitted an initial assessment of the strength of each near-neighbor interaction. The parameter sets describing the effects of discrete XB-XB or XB-RU interactions failed to adequately fit the in vitro contractility data in either murine or porcine myocardium. However, the Ca2+ dependence of ktr in murine and porcine ventricular myocardium was well fit by parameter sets incorporating the RU-RU cooperative interaction. Our results indicate that a significantly stronger RU-RU interaction is present in porcine ventricular myocardium compared with murine ventricular myocardium and that the relative strength of the near-neighbor RU-RU interaction contributes to species-specific myocardial contractile dynamics in small and large mammals.

心肌肌力的协同激活和失活机制从涉及肌钙蛋白-肌球蛋白调节单元(RU)和交叉桥(XB)的局部近邻相互作用扩展到横跨肌节的更全面的相互作用。为了更好地了解这些机制在小型和大型哺乳动物心脏中的作用,我们采用了一种简化的数学方法来评估三种近邻合作性相互作用的贡献,即 RU 诱导的 RU 激活(RU-RU)、横桥诱导的横桥结合(XB-XB)和 XB 诱导的 RU 激活(XB-RU)。我们测量了小鼠和孔雀石膜化心室心肌中力量再发展速率常数的 Ca2+ 和活化依赖性。通过对这三种近邻相互作用进行数学建模,得出了 RU-RU 和 XB-RU 速率系数(kon 和 koff)以及 XB-XB 速率系数(f 和 f')的非线性表达式,这些非线性表达式描述了产生力的交桥的附着情况。通过推导单一合作系数参数(u = RU-RU、w = XB-RU、v = XB-XB),可以初步评估每种近邻相互作用的强度。描述离散 XB-XB 或 XB-RU 相互作用效果的参数集未能充分拟合鼠或猪心肌的体外收缩力数据。然而,包含 RU-RU 协同作用的参数集却能很好地拟合小鼠和猪心室心肌中 ktr 的 Ca2+ 依赖性。我们的研究结果表明,与小鼠心室心肌相比,猪心室心肌中存在明显更强的 RU-RU 相互作用,而且近邻 RU-RU 相互作用的相对强度导致了小型和大型哺乳动物心肌收缩动力学的物种特异性。
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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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