Myosin-linked mechanisms for the regulation of muscle contraction

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-锻炼它们-确实使它们更强壮，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。这项提案旨在发现是什么控制着健康肌肉的力量，因为如果我们理解了这一点，我们也许能够设计出一种药物来增强虚弱肌肉的力量。 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，人们发现还有另一种类型的肌肉控制，它通过改变粗肌丝的结构来发挥作用，这可以改变ON和OFF状态。换句话说，这些粗丝结构的变化可以控制肌肉的力量，也可以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，了解如何控制肌肉的关闭状态可能有助于对抗一个非常不同的健康问题，使我们能够使用肌肉燃烧一些不需要的卡路里。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-我们不知道粗丝的结构如何变化，以及是什么控制了这些变化。不过，我们确实知道哪些蛋白质参与其中，以及它们在肌节中的大致位置。在这个项目中，我们将应用我们开发的一种新方法，用小荧光分子标记粗丝蛋白，报告肌肉细胞内部蛋白质结构的变化。我们对这种方法的初步测试表明，它能够回答有关粗纤维结构的变化如何控制肌肉性能的一些关键问题：在分子水平上粗纤维的OFF和ON结构之间有何区别？这些粗肌丝的结构变化是如何控制肌肉力量的？粗灯丝结构本身是如何控制的？这种控制与细丝中的钙离子转换有什么关系呢？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。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。

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 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 seeks to discover what controls the strength of healthy muscles because, if we understood that, we might be able to design a drug to 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 it has become apparent that there is another type of muscle control that works by changing the structure of the thick filaments, and this can alter both the ON and the OFF states. In other words, these changes in thick filament structure can control the strength of a muscle, but also how much energy a muscle uses when it is resting. Since about a third of the weight of our bodies is muscle, understanding how to control the OFF state of muscle might be useful in combatting a very different health problem, allowing us to use muscles to burn off some unwanted calories. At present we don't know how these OFF and ON states of muscle are controlled- we don't know exactly how the structure of the thick filament changes, and what controls those changes. We do know which proteins are involved, though, and roughly where they are in the sarcomere. In this project we will apply a new method that we developed to tag the thick filament proteins with small fluorescent molecules that report changes in protein structure from inside muscle cells. Our preliminary tests with this method shows that it is capable of answering some key questions about how changes in in thick filament structure control muscle performance: What is the difference between the OFF and ON structures of the thick filaments at the molecular level? How do these structural changes in the thick filament control the muscle strength? How is thick filament structure itself controlled? How is that control related to the calcium switch in the thin filaments? 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.