The mechanism of stretch activation in muscle: a multidisciplinary approach

了解肌肉的工作原理是很重要的，这不仅有助于我们深入理解生理学，也有助于我们设计治疗肌肉疾病的新疗法。特别是，了解心肌如何工作对预防和治疗所有心肌病至关重要。现在已知肌肉收缩的调节涉及两种不同的机制，一种由钙触发，另一种由机械拉伸启动。虽然前者研究得相对较好，但后者却知之甚少。这个应用程序的目的是了解所有肌肉的拉伸激活机制。我们计划使用昆虫飞行肌，因为在这些肌肉中，拉伸激活起主要作用，因此可以在没有其他主要钙激活机制的掩蔽效应的情况下进行研究。我们希望找出所有横纹肌的共同调节方面。我们将使用一只巨大的亚洲水虫，因为它的飞行肌肉特别适合生理学研究，这要归功于它们可观的尺寸。对巨型水虫的飞行肌肉进行了开创性的研究，其中一些是由这个团队的成员进行的。飞行肌是所有肌肉中结构最有序的，这使得它在收缩时非常适合跟随结构变化。我们将利用两个团队的专业知识，一个在伦敦，另一个在约克，这两个团队都有长期的经验，研究肌肉蛋白质，使用不同但互补的分析方法来解决这个具有挑战性和迷人的问题。两个团队都在各自的学科中拥有最先进的设备，并且都在开发研究生物分子，生物分子相互作用和途径的分析方法方面拥有多年的经验。这两个团队之前也曾合作过，发表的研究结果增加了我们对肌肉功能的理解。该项目具有巨大的前景，不仅对理解拉伸激活的机制，而且为未来开发能够干预肌肉激活的化合物提供了新的工具。心肌和昆虫飞行肌都有节奏地收缩，并通过拉伸激活。因此，我们的研究将帮助我们理解收缩的调节是如何演变的；我们将更深入地了解心脏和其他肌肉的工作方式。这最终有可能增加我们对人类心肌病病因的理解。

Understanding how muscle works is important, both for our in depth comprehension of physiology, and to allow us to design new therapies to cure muscle diseases. In particular, understanding how cardiac muscle, works is essential for the prevention and treatment of all cardiomyopathies. Regulation of muscle contraction is now known to involve two different mechanisms, one triggered by calcium, the second initiated by mechanical stretch. While the first is relatively well studied, very little is known about the second.The goal of this application is to understand the mechanism of stretch activation in all muscles. We plan to use insect flight muscle, because in these muscles, stretch activation plays a predominant role, and can thus be studied in the absence of the masking effects of the otherwise predominant calcium-activation mechanism. We hope to find out what aspects of regulation are common to all striated muscles. We will use a giant Asiatic waterbug, since its flight muscles are particularly suitable for physiological studies, thanks to their appreciable size. There have been ground breaking studies on the flight muscle of the giant waterbug, some of which were carried out by members of this team. The flight muscle has the most ordered structure of any muscle, which makes it ideal for following structural changes when it contracts.We will exploit the expertise of two teams, one in London and the other in York, both of which have previous long experience of working on muscle proteins using different but complementary analytical approaches to tackle this challenging and fascinating problem. Both teams have state-of-the-art facilities in their own discipline, and both have many years experience in developing analytical methods for studying biomolecules, and biomolecular interactions and pathways. The two teams have also been working in collaboration before, producing published results that have increased our understanding of muscle functioning.The project holds enormous promise, not only for understanding the mechanism of stretch activation, but also for providing new tools for the future development of compounds able to intervene in muscle activation. Both cardiac muscle and insect flight muscle contract rhythmically and are activated by stretch. Thus, our research will help us to understand how the regulation of contraction has evolved; we will gain more insight into the way cardiac and other muscles work. This has ultimately the potential to increase our understanding of the causes of human cardiomyopathies.