Regulation of Contraction by the thick filaments in skeletal muscle

骨骼肌粗丝对收缩的调节

• 批准号: MR/R01700X/1
• 负责人: Malcolm Irving
• 金额: $ 75.99万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR01700X%2F1
• 关键词: Regulation; Contraction; thick; filaments; skeletal

Muscles make us mobile, and mobility is a major factor determining our quality of life. Unfortunately our muscles get weaker as we get older, and everyday tasks like walking, climbing stairs or even getting up out of a chair get more difficult. Many diseases also lead to more severe forms of muscle weakness, and some of these affect young children. In general there is no effective treatment for muscle weakness. Using muscles- exercising them- does make them stronger, but this is not always possible, particularly for those suffering from diseases that affect the muscles. This proposal follows up some new discoveries about how the strength of healthy muscles is controlled. It aims to understand those new control mechanisms better so that it will be possible to design and test potential drugs to intervene in muscle control and boost the strength of weak muscles. Muscles are built from long strings of a basic microscopic building block called a sarcomere. Each sarcomere contains an array of two types of filament, one wider than the other, and these are called thick and thin filaments. The relative sliding of these two sets of filaments is responsible for muscle shortening. When a signal from the brain travels along a nerve and reaches a muscle, it triggers release of calcium from stores inside the muscle cell. The calcium binds to the thin filaments, causing a change in their structure that allows the filaments to slide, and the muscle contracts. This change in thin filament structure is quite well understood, but it works like an OFF/ON switch- it controls when the muscle contracts, but not how strongly. Recently another type of muscle control was discovered that works by changing the structure of the thick filaments. These changes in thick filament structure control the strength and speed of muscle activation, and how fast they relax, but we still know very little about how they work. Thick filament structure also controls how much energy a muscle uses when it is resting. Since about a third of the weight of our bodies is muscle, understanding how the OFF state of muscle is controlled might help to combat some very different health problems, by allowing muscles to be used to burn off unwanted calories. At present we don't know how these OFF and ON states of muscle are controlled- we don't know how the structure of the thick filament changes, and what controls those changes. In this project we will apply the technical advances provided by two of the brightest X-ray sources available worldwide (in France and the USA) and a fluorescence based method that we developed to tag the thick filament proteins to measure the changes in thick filament structure when isolated muscle cells contract. These methods will allow us to answer the key questions about how the structure of the thick filaments controls the strength and speed of muscle contraction and, no less important for the way muscles are used in the body, how the speed of muscle relaxation is controlled.The answers to these questions will allow us to develop a detailed picture of how the OFF and ON states are controlled by changes in thick filament structure in healthy muscle. This in turn will enable us to suggest ways in which these states might be controlled by drugs, and to develop ways to assess the value of potential new drugs. Finally, since very similar changes in thick filament structure occur in heart muscle using the same protein components, we expect that the results of this project will also be useful in guiding an analogous approach to controlling the strength of heart muscle, and therefore in developing potential new treatments for heart disease.

肌肉使我们能够移动的，而移动性是决定我们生活质量的主要因素。不幸的是，随着年龄的增长，我们的肌肉变得越来越弱，日常任务，如走路，爬楼梯，甚至从椅子上站起来变得更加困难。许多疾病也会导致更严重的肌肉无力，其中一些会影响幼儿。一般来说，没有有效的治疗肌肉无力。使用肌肉--锻炼肌肉--确实会让它们变得更强壮，但这并不总是可能的，特别是对于那些患有影响肌肉的疾病的人来说。该提案遵循了有关如何控制健康肌肉力量的一些新发现。它的目的是更好地了解这些新的控制机制，以便有可能设计和测试潜在的药物来干预肌肉控制和增强弱肌肉的力量。 肌肉是由一种叫做肌节的基本微观结构单元组成的。每一个肌节都包含两种类型的肌丝，一种比另一种宽，这些被称为粗肌丝和细肌丝。这两组细丝的相对滑动是肌肉缩短的原因。当来自大脑的信号沿着神经传播并到达肌肉时，它会触发肌肉细胞内钙的释放。钙与细丝结合，导致其结构发生变化，使细丝滑动，肌肉收缩。这种细丝结构的变化是很好理解的，但它的工作原理就像一个关闭/打开开关-它控制肌肉何时收缩，但不控制强度。最近发现了另一种类型的肌肉控制，通过改变粗丝的结构来工作。这些粗丝结构的变化控制着肌肉激活的强度和速度，以及它们放松的速度，但我们对它们如何工作仍然知之甚少。粗丝结构也控制肌肉在休息时使用多少能量。由于我们身体重量的三分之一是肌肉，了解肌肉的关闭状态是如何控制的可能有助于对抗一些非常不同的健康问题，通过允许肌肉被用来燃烧不需要的卡路里。目前，我们还不知道肌肉的这些关闭和打开状态是如何控制的-我们不知道粗细丝的结构如何变化，以及是什么控制了这些变化。在这个项目中，我们将应用全球最亮的两个X射线源（法国和美国）提供的技术进步，以及我们开发的标记粗丝蛋白的荧光方法，以测量分离的肌细胞收缩时粗丝结构的变化。这些方法将使我们能够回答有关粗丝结构如何控制肌肉收缩的强度和速度的关键问题，并且对于肌肉在体内的使用方式同样重要，肌肉放松的速度是如何控制的。这些问题的答案将使我们能够详细了解健康人的粗丝结构变化如何控制OFF和ON状态。肌肉.这反过来将使我们能够提出药物控制这些状态的方法，并开发评估潜在新药价值的方法。最后，由于使用相同的蛋白质组分在心肌中发生了非常相似的粗丝结构变化，我们预计该项目的结果也将有助于指导控制心肌强度的类似方法，从而开发潜在的心脏病新疗法。

项目成果

Dependence of thick filament structure in relaxed mammalian skeletal muscle on temperature and interfilament spacing.

• DOI: 10.1085/jgp.202012713
• 发表时间: 2021-03-01
• 期刊: The Journal of general physiology
• 作者: Caremani M;Fusi L;Linari M;Reconditi M;Piazzesi G;Irving TC;Narayanan T;Irving M;Lombardi V;Brunello E
• 通讯作者: Brunello E

Activation of skeletal muscle is controlled by a dual-filament mechano-sensing mechanism.

• DOI: 10.1073/pnas.2302837120
• 发表时间: 2023-05-30
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Brunello, Elisabetta;Marcucci, Lorenzo;Irving, Malcolm;Fusi, Luca
• 通讯作者: Fusi, Luca

Myosin-based regulation of twitch and tetanic contractions in mammalian skeletal muscle.

• DOI: 10.7554/elife.68211
• 发表时间: 2021-06-14
• 期刊: eLife
• 影响因子: 7.7
• 作者: Hill C;Brunello E;Fusi L;Ovejero JG;Irving M
• 通讯作者: Irving M

Dependence of myosin filament structure on intracellular calcium concentration in skeletal muscle.

• DOI: 10.1085/jgp.202313393
• 发表时间: 2023-12-04
• 期刊: The Journal of general physiology

Myosin motors that cannot bind actin leave their folded OFF state on activation of skeletal muscle.

• DOI: 10.1085/jgp.202112896
• 发表时间: 2021-11-01
• 期刊: The Journal of general physiology
• 作者: Reconditi M;Brunello E;Fusi L;Linari M;Lombardi V;Irving M;Piazzesi G
• 通讯作者: Piazzesi G