Regulation of Contraction by the thick filaments in skeletal muscle

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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.