Quantifying inter-species differences in contractile function through biophysical modelling.
Quantifying inter-species differences in contractile function through biophysical modelling.
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通过生物物理建模量化收缩功能的物种间差异。
DOI：
10.1113/jphysiol.2014.279232
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Tøndel K
中科院分区：
文献类型：
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作者：
Tøndel K
关键点为了将动物模型的数据转化为临床应用，分析和量化物种间特定生理机制的差异和相关性是非常重要的。我们提出了一种新的方法，用于量化生物物理模型参数方面的物种间差异，并将其应用于阐明小鼠，我们的结果表明，与钙结合肌钙蛋白C的敏感性和协同性以及原肌球蛋白/交联桥结合动力学的激活和松弛速率相关的参数在小鼠之间差异最显著，大鼠和人类。我们的研究结果预测crossbridge绑定是最慢的人和最快的mouse.AbstractAnimal模型和测量经常被用来指导和评估临床干预。在这种情况下，了解生理学的种间差异对于理解动物实验测定的局限性和相关性至关重要，以便为临床应用提供信息。人们已经投入了大量的精力来研究心脏收缩蛋白的结构和功能，以及这些蛋白的差异如何转化为肌肉的功能特性。然而，将这些知识整合到定量描述中，形式化并突出物种间在动力学和生理机制调节方面的差异，仍然具有挑战性。在这项研究中，我们提出并应用了一种新的方法来量化小鼠，大鼠和人类之间的种间差异。假设保守的基础收缩的基本生理机制，bioprophically为基础的计算模型拟合模拟实验记录的表型从多个物种。物种之间的表型差异，然后简洁地量化为生物物理模型参数值的差异。这提供了定量建立基于动物的实验和计算模型的人类相关性的潜力，以用于临床应用。我们的研究结果表明，相关的参数的敏感性和协同性的钙结合肌钙蛋白C和激活和松弛率的原肌球蛋白/crossbridge结合动力学小鼠，大鼠和人类之间的差异最显着，而例如，参考张力，如预期的那样，显示物种之间只有微小的差异。因此，虽然由于观察到的钙瞬变的巨大差异而证实了钙敏感性的预期种间差异，但我们的结果也表明了协同机制中更多的意外差异。具体而言，随着主动张力的增加，小鼠的钙与肌钙蛋白C的解结合率的降低远低于大鼠和人。我们的研究结果还预测了crossbridge结合在人类中最慢，在小鼠中最快。
Key pointsTo facilitate translation of data from animal models into clinical applications, it is important to analyse and quantify the differences and relevance of specific physiological mechanisms between species.We propose a novel approach for the quantification of inter‐species differences in terms of biophysical model parameters and apply this to elucidate the differences in cardiac contraction mechanisms between mouse, rat and human.Our results indicate that the parameters related to the sensitivity and cooperativity of calcium binding to troponin C and the activation and relaxation rates of tropomyosin/crossbridge binding kinetics differ most significantly between mouse, rat and human.Our results predict crossbridge binding to be slowest in human and fastest in mouse.AbstractAnimal models and measurements are frequently used to guide and evaluate clinical interventions. In this context, knowledge of inter‐species differences in physiology is crucial for understanding the limitations and relevance of animal experimental assays for informing clinical applications. Extensive effort has been put into studying the structure and function of cardiac contractile proteins and how differences in these translate into the functional properties of muscles. However, integrating this knowledge into a quantitative description, formalising and highlighting inter‐species differences both in the kinetics and in the regulation of physiological mechanisms, remains challenging. In this study we propose and apply a novel approach for the quantification of inter‐species differences between mouse, rat and human. Assuming conservation of the fundamental physiological mechanisms underpinning contraction, biophysically based computational models are fitted to simulate experimentally recorded phenotypes from multiple species. The phenotypic differences between species are then succinctly quantified as differences in the biophysical model parameter values. This provides the potential of quantitatively establishing the human relevance of both animal‐based experimental and computational models for application in a clinical context. Our results indicate that the parameters related to the sensitivity and cooperativity of calcium binding to troponin C and the activation and relaxation rates of tropomyosin/crossbridge binding kinetics differ most significantly between mouse, rat and human, while for example the reference tension, as expected, shows only minor differences between the species. Hence, while confirming expected inter‐species differences in calcium sensitivity due to large differences in the observed calcium transients, our results also indicate more unexpected differences in the cooperativity mechanism. Specifically, the decrease in the unbinding rate of calcium to troponin C with increasing active tension was much lower for mouse than for rat and human. Our results also predicted crossbridge binding to be slowest in human and fastest in mouse.