Regulation of Contraction by the thick filaments in skeletal muscle

肌肉使我们活动自如，而活动自如是决定我们生活质量的一个主要因素。不幸的是，随着年龄的增长，我们的肌肉会变得越来越弱，像走路、爬楼梯甚至从椅子上站起来这样的日常活动都会变得越来越困难。许多疾病还会导致更严重形式的肌肉无力，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——确实能让它们变得更强壮，但这并不总是可行的，尤其是对那些患有影响肌肉疾病的人来说。这项提议是在一些关于健康肌肉的力量是如何被控制的新发现之后提出的。它的目的是更好地理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，增强弱肌肉的力量。肌肉是由一种叫做肌节的基本微观构件的长串构成的。每个肌节包含两种类型的纤维，一种比另一种宽，这两种被称为粗纤维和细纤维。这两组纤维的相对滑动是导致肌肉缩短的原因。当来自大脑的信号沿着神经到达肌肉时，它会触发肌肉细胞内储存的钙的释放。钙与细丝结合，导致细丝的结构发生变化，从而使细丝滑动，肌肉收缩。细丝结构的这种变化是很容易理解的，但它的工作原理就像一个开关——它控制肌肉收缩的时间，而不是收缩的强度。最近发现了另一种肌肉控制方式，它通过改变粗纤维的结构起作用。这些粗纤维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，但我们对它们的工作原理仍然知之甚少。粗大的纤维结构也控制着肌肉在休息时消耗的能量。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被控制的，可能有助于对抗一些非常不同的健康问题，通过让肌肉被用来燃烧不需要的卡路里。目前我们还不知道这些肌肉的开关状态是如何被控制的——我们不知道粗丝的结构是如何变化的，以及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（在法国和美国）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，以测量分离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以下关键问题：粗纤维的结构如何控制肌肉收缩的力量和速度，以及肌肉放松的速度如何被控制，这对人体使用肌肉的方式同样重要。这些问题的答案将使我们能够详细了解健康肌肉中粗丝结构的变化如何控制OFF和ON状态。反过来，这将使我们能够提出这些状态可能被药物控制的方法，并开发评估潜在新药价值的方法。最后，由于心肌中使用相同的蛋白质成分也会发生非常相似的粗丝结构变化，我们期望这个项目的结果也将有助于指导类似的方法来控制心肌的力量，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.