Regulation of Contraction by the thick filaments in skeletal muscle

肌肉使我们能够移动，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，我们的肌肉会变得虚弱，走路、爬楼梯甚至从椅子上站起来等日常任务变得更加困难。许多疾病还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的方法。使用肌肉--锻炼肌肉--确实会让他们变得更强壮，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。这项建议是对一些关于如何控制健康肌肉力量的新发现的补充。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，增强脆弱肌肉的力量。肌肉是由一种名为肌节的基本显微构造块组成的长绳组成的。每个肌节包含两种类型的细丝，一种比另一种更宽，这些被称为粗丝和细丝。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储存的钙的释放。钙结合到细丝上，引起细丝结构的变化，使细丝滑动，肌肉收缩。细丝结构的这种变化是很好理解的，但它的工作原理就像一个开关--它控制肌肉何时收缩，但不控制收缩的强度。最近，另一种肌肉控制方式被发现，它通过改变粗丝的结构来发挥作用。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，但我们仍然对它们的工作原理知之甚少。粗大的细丝结构还控制着肌肉在休息时消耗的能量。由于我们身体大约三分之一的重量是肌肉，了解肌肉的关闭状态是如何控制的，通过允许肌肉被用来燃烧不需要的卡路里，可能有助于对抗一些截然不同的健康问题。目前，我们不知道肌肉的这些开关状态是如何控制的--我们不知道粗丝的结构是如何变化的，也不知道是什么控制了这些变化。在这个项目中，我们将应用世界上两个最亮的X射线源(法国和美国)提供的技术进步，以及我们开发的一种基于荧光的方法来标记粗丝蛋白，以测量当分离的肌肉细胞收缩时粗丝结构的变化。这些方法将使我们能够回答关于粗丝结构如何控制肌肉收缩的强度和速度的关键问题，以及对肌肉在身体中的使用方式同样重要的是如何控制肌肉放松的速度的关键问题。对这些问题的回答将使我们能够详细地描述健康肌肉中粗丝结构的变化是如何控制开关状态的。这反过来将使我们能够提出这些州可能受到药物控制的方法，并开发出评估潜在新药价值的方法。最后，由于使用相同蛋白质成分的心肌中粗丝结构的变化非常相似，我们预计该项目的结果也将有助于指导类似的方法来控制心肌力量，从而开发潜在的心脏病新疗法。

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.