The mechanism of stretch activation in muscle: a multidisciplinary approach

肌肉拉伸激活机制：多学科方法

• 批准号: BB/M006824/1
• 负责人: Annalisa Pastore
• 金额: $ 43.07万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM006824%2F1
• 关键词: mechanism; stretch; activation; muscle; multidisciplinary

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.

了解肌肉如何工作是很重要的，无论是对我们深入了解生理学，并允许我们设计新的疗法来治疗肌肉疾病。特别是，了解心肌如何工作对于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，第二种由机械拉伸引发。虽然第一个是相对较好的研究，很少有人知道第二个。这个应用程序的目标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，拉伸激活起着主导作用，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。我们希望找出哪些方面的调节是共同的所有横纹肌。我们将使用一个巨大的亚洲水蝽，因为它的飞行肌肉特别适合于生理学研究，这要归功于它们可观的大小。对巨型水蝽的飞行肌肉进行了开创性的研究，其中一些是由该团队的成员进行的。飞行肌具有任何肌肉中最有序的结构，这使得它在收缩时非常适合跟踪结构变化。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，这两个团队都有使用不同但互补的分析方法研究肌肉蛋白的长期经验，以解决这个具有挑战性和迷人的问题。两个团队都拥有各自学科的最先进设施，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。这两个团队之前也一直在合作，发表的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，不仅有助于理解拉伸激活的机制，而且还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律地收缩，并被拉伸激活。因此，我们的研究将帮助我们了解收缩的调节是如何演变的;我们将更多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原因的理解。

项目成果

Expression and Purification of ZASP Subdomains and Clinically Important Isoforms: High-Affinity Binding to G-Actin.

• DOI: 10.1021/acs.biochem.7b00067
• 发表时间: 2017-04-11
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Watts NR;Zhuang X;Kaufman JD;Palmer IW;Dearborn AD;Coscia S;Blech-Hermoni Y;Alfano C;Pastore A;Mankodi A;Wingfield PT
• 通讯作者: Wingfield PT

Toward Understanding the Molecular Bases of Stretch Activation: A STRUCTURAL COMPARISON OF THE TWO TROPONIN C ISOFORMS OF LETHOCERUS.

• DOI: 10.1074/jbc.m116.726646
• 发表时间: 2016-07-29
• 期刊: The Journal of biological chemistry
• 作者: Sanfelice D;Sanz-Hernández M;de Simone A;Bullard B;Pastore A
• 通讯作者: Pastore A

Molecular Characterisation of Titin N2A and Its Binding of CARP Reveals a Titin/Actin Cross-linking Mechanism.

• DOI: 10.1016/j.jmb.2021.166901
• 发表时间: 2021-04-30
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Zhou T;Fleming JR;Lange S;Hessel AL;Bogomolovas J;Stronczek C;Grundei D;Ghassemian M;Biju A;Börgeson E;Bullard B;Linke WA;Chen J;Kovermann M;Mayans O
• 通讯作者: Mayans O

Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I.

titin I波段中的单核苷酸多态性触发的病理机制的探索：心肌病连接的突变T2580i。

• DOI: 10.1098/rsob.160114
• 发表时间: 2016-09
• 期刊: Open biology
• 影响因子: 5.8
• 作者: Bogomolovas J;Fleming JR;Anderson BR;Williams R;Lange S;Simon B;Khan MM;Rudolf R;Franke B;Bullard B;Rigden DJ;Granzier H;Labeit S;Mayans O
• 通讯作者: Mayans O

Hybrid Methods in Iron-Sulfur Cluster Biogenesis.

• DOI: 10.3389/fmolb.2017.00012
• 发表时间: 2017
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Prischi F;Pastore A
• 通讯作者: Pastore A