Mechanobiology in cardiac mechanics.
Mechanobiology in cardiac mechanics.
复制标题
心脏力学中的机械生物学。
DOI：
10.1007/s12551-021-00827-4
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发表时间：
2021-10
影响因子：
--
通讯作者：
Sheetz M
中科院分区：
文献类型：
--
作者：
Sheetz M
心脏的收缩-松弛循环是身体中最强大的机械系统之一，它通过改变机械参数来快速适应身体的需要。在许多方面，我们可以将心脏系统视为一台复杂的机器，并可以使用工程方法来描述其功能。心脏的经典生理学也侧重于了解功能，但光学显微镜和纳米工程中的新分子水平工具现在使人们能够更深入地了解生理学。机械生物学领域的重点是机械活动如何在分子水平上改变生物系统，以及这些系统如何反过来控制机械参数。在机械活动的情况下，锻炼对心脏、癌症患者和衰老都有明显的好处，但我们不知道分子水平上的联系。为什么经常锻炼有益于心脏？关于运动对癌症和衰老的益处，我们在分子水平上已经有了一些初步的线索；然而，关于运动如何影响心血管表现，我们知之甚少。与通常将蛋白质与过程联系在一起的组学方法不同，对过程的机械生物学理解解释了力和机械活动如何通过改变蛋白质的活动来调节过程。换句话说，机械活动是大多数生物系统的基本组成部分，它被转化为蛋白质活动的生化变化。此外，从逻辑上讲，如果心脏系统的机械参数通常是受控制的，那么细胞机械传感系统必须能够直接或间接地测量该参数。挑战在于了解心脏活动的变化在短期内是如何控制的，然后系统如何适应长期活动的综合水平。通过对分子机械生物学的介绍，我将介绍从分子到细胞尺度的机械传感的例子，以及它们如何在细胞和组织水平上整合。机制生物学在系统水平上的一个重要元素是细胞的生理状态：即细胞处于衰老状态、癌症状态或正常细胞状态(Sheetz)。机械生物学方法的背景在“细胞作为机器”(Sheetz和Yu，剑桥大学出版社，2018年)中进行了讨论，其中考虑了细胞状态和支持重要细胞功能的分子系统。机械生物学中的一个主要挑战是理解机械活动转化为细胞功能变化的过程。这里特别相关的是锻炼对心脏性能的好处。这在许多情况下都可以看到，有多种因素造成了这种情况。此外，运动将使癌症患者受益，并将逆转衰老的一些不利影响。运动将导致心脏活动增加，从分子到细胞水平的许多机械感觉系统都能感觉到这一点，心脏和血管系统都能感觉到这一点。在心脏系统的分子水平上，蛋白质能够测量应力和应变，并产生适当的应力和应变大小的信号，可以调节细胞的收缩能力和其他参数。蛋白质传感器通常是被动系统，可以提供局部参数的瞬时测量，如收缩期间细胞-细胞连接处的应力和松弛期间肌节的应变。交界处的大压力可以激活信号系统，从而降低收缩能力，或随着时间的推移激活交界处的重塑，以更好地支持更大的应力。所涉及的蛋白质及其感觉机制目前尚不清楚；然而，机械敏感通道Piezo1已被牵涉到血管系统的转导过程(山毛榉)。在应变传感器的情况下，松弛过程中大范围的titin可以展开更多的titin结构域，这些结构域可以向细胞发送信号。Titin中可能存在两种不同的应变传感机制。肌动蛋白激活域被菌株激活，但活体内的底物未知(Linke)。在Titin的主干上有许多Ig结构域，它们在不同的力下展开，展开可以导致蛋白质的结合，然后激活酶途径来改变收缩周期，从而提供适当的应变水平(Ait-Mou等人；Granzier等人；Granzier等人)。细胞-基质黏附蛋白talin具有11个与另一种黏附蛋白vinculin的隐蔽结合位点，这是通过talin分子中结构域的展开而揭示的(姚等人)。由于一些结构域比其他结构域以较低的力展开，小应变将优先展开这些结构域，使该系统成为Titin预期的拉伸程度的极佳传感器。因为有许多Titin分子的有序阵列，所以对应变的感知可以对肌节长度的微小变化非常敏感。不用说，Titin只是控制肌节长度的监管系统的一部分。随着人们更深入地了解该系统的工作，很明显，许多额外的机械感觉元件参与了维持心脏系统功能的工作。
The contraction-relaxation cycle of the heart is one of the most robust mechanical systems in the body that adapts rapidly to the body’s needs by changing mechanical parameters. In many respects, we can consider the cardiac system as a complex machine and can use engineering approaches to describe its function. The classical physiology of the heart also focused on understanding function but the new molecular level tools in light microscopy and nanoengineering now enable a deeper understanding of the physiology. The field of mechanobiology has emerged with a focus on how mechanical activity alters biological systems at the molecular level and how those systems in turn control mechanical parameters. In the case of mechanical activity, there are clearly benefits of exercise for the heart, for cancer patients, and for aging but we do not understand the links at a molecular level. Why does regular exercise benefit the heart? We have some preliminary clues at a molecular level about the benefits of physical activity in the cases of cancer and aging; however, there is less known about how exercise affects cardiovascular performance. Unlike the omics approaches which generally link proteins to processes, a mechanobiological understanding of a process explains how forces and mechanical activity will regulate the process through modifications of protein activities. In other words, mechanical activity is an essential component of most biological systems that is transduced into biochemical changes in protein activity. Further, it follows logically that if a mechanical parameter of the cardiac system is typically controlled, then cellular mechanosensing systems must be able to directly or indirectly measure that parameter. The challenge is to understand how changes in activity of the heart are controlled in the short term and then how the system adapts to the integrated level of activity over the longer term. By way of introduction to molecular mechanobiology, I will present examples of mechanosensing from the molecular to the cellular scale and how they may be integrated at the cell and tissue levels. An important element of Mechanobiology at the system level is the physiological state of the cell: i.e., the cell in a senescent state, a cancer state, or a normal cell state (Sheetz). The background for the mechanobiological approach is discussed in “The Cell as a Machine” (Sheetz and Yu, Cambridge Univ Press, 2018), which considers cell states and the molecular systems underlying the important cellular functions. A major challenge in mechanobiology is the understanding of the transduction of mechanical activity into changes in cell function. Of particular relevance here is the benefit of exercise to cardiac performance. This has been seen in many cases and there are a variety of factors that contribute. Further, exercise will benefit cancer patients and will reverse some of the adverse effects of aging. Exercise will cause increased cardiac activity that will be sensed by many mechanosensory systems from a molecular to a cellular level both in the heart and in the vasculature. At a molecular level in cardiac systems, proteins are able to measure stress and strain and to generate appropriate signals of the magnitude of stress and strain that can regulate the cellular contractility and other parameters. The protein sensors are generally passive systems that give a transient measure of local parameters such as the stress at cell-cell junctions during contraction and the strain of the sarcomeres during relaxation. Large stresses at the junctions can activate signaling systems that can reduce contractility or over time activate remodeling of the junctions to better support larger stresses. The proteins involved and their sensory mechanisms are not known currently; however, the mechanosensitive channel, Piezo1, has been implicated in the transduction process in the vasculature (Beech). In the case of strain sensors, large stretches of titin during relaxation can unfold more titin domains that can send signals to the cell. Two different mechanisms of strain sensing are likely in titin. The titin kinase domain is activated by strain but the substrates of the kinase are not know in vivo (Linke). In the backbone of titin are many Ig domains that unfold at different forces and unfolding could cause the binding of proteins that would then activate enzymatic pathways to alter the contractile cycle to give the proper level of strain (Ait-Mou et al.; Granzier et al.; Granzier et al.). The cell-matrix adhesion protein, talin, has eleven cryptic binding sites for another adhesion protein, vinculin, that are revealed by the unfolding of domains in the talin molecule (Yao et al.). Since some domains unfold at lower forces than others, small strains will preferentially unfold those domains, making the system an excellent sensor of the extent of stretch as expected for titin. Because there is an ordered array of many titin molecules, the sensing of strain can be very sensitive to small changes in sarcomere length. Needless to say, titin is only one part of the regulatory system that controls sarcomere length. As one goes more deeply into the working of the system, it is evident that many additional mechanosensory elements are involved in maintaining a functioning cardiac system.
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影响因子：
21.3
作者：
Wolfenson H;Meacci G;Liu S;Stachowiak MR;Iskratsch T;Ghassemi S;Roca-Cusachs P;O'Shaughnessy B;Hone J;Sheetz MP
通讯作者：
Sheetz MP
影响因子：
41.2
作者：
Yang, Bo;Wolfenson, Haguy;Sheetz, Michael P.
通讯作者：
Sheetz, Michael P.
影响因子：
20.1
作者：
Granzier HL;Radke MH;Peng J;Westermann D;Nelson OL;Rost K;King NM;Yu Q;Tschöpe C;McNabb M;Larson DF;Labeit S;Gotthardt M
通讯作者：
Gotthardt M
影响因子：
7.8
作者：
Chen XK;Yi ZN;Wong GT;Hasan KMM;Kwan JS;Ma AC;Chang RC
通讯作者：
Chang RC
影响因子：
16.6
作者：
Yao M;Goult BT;Klapholz B;Hu X;Toseland CP;Guo Y;Cong P;Sheetz MP;Yan J
通讯作者：
Yan J