When a zebrafish muscle contracts, the force of that contraction tells the muscle to grow—and researchers want to know exactly how that message gets sent. Skeletal muscle makes up 40% of body mass, and its loss is a serious problem in diseases like cancer, kidney failure, and rheumatoid arthritis, as well as in ageing and hospitalisation. Exercise prevents wasting by promoting growth, but how the body decides how much muscle to build is unknown. This project aims to uncover the feedback mechanism: how muscle tissue detects force and responds by growing. The team will study young zebrafish, which are transparent and genetically easy to manipulate, allowing them to watch muscle growth in a living animal and measure the forces involved. They will examine the protein complexes at muscle fibre ends that transmit force and may act as force detectors. They will also investigate how muscle stem cells form, where they reside, and how force regulates their behaviour to coordinate growth and repair. This is fundamental science. Understanding how force drives growth in skeletal muscle could illuminate similar processes in bone, heart, and skin, with implications for regenerative medicine. Past discoveries in fish, mice, and humans have already shown that early muscle formation is remarkably similar across species—this work extends that insight into later growth.
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Skeletal muscle makes up 40% of our body mass and its maintenance is essential to a good quality of life. In muscle diseases, cancer, chronic kidney failure, AIDS and rheumatoid arthritis, and particularly in older or hospitalised people, muscle wasting is a serious problem. The physical force of exercise prevents wasting by promoting muscle growth. How the body decides what is an appropriate amount of muscle is unknown, but a likely mechanism is feedback from the force of muscle contraction. We want to find out how muscle tissue detects force and responds by growing. In the past, we have discovered how early muscle is made in similar ways in fish, mice and people. Now, we want to study the role of force in later muscle growth. So our first aim is determine how muscle normally grows and how force and other signals influence growth. We will use young zebrafish because they are a) transparent, so that we can study muscle growth in the living animal, b) easy to manipulate genetically, so we can find out what genes control growth, c) small and accessible, so we can measure and impose forces in the living muscle. These things are more difficult to do in mammals. Our second aim is to understand how muscle detects force and uses the information to orchestrate growth. Muscle fibre ends transmit force to adjacent tissues by means of a complex set of proteins that form attachments to neighbouring cells. Evidence leads us to hypothesise that these attachments are also force-detectors that initiate the process of growth in response to certain kinds of contractile activity. We will study the composition and dynamics of the protein complex at fibre ends and test its role in force detection and growth response. Muscle is continually damaged during life and is normally repaired by stem cells, which also contribute to growth. Our third aim is to understand how muscle stem cells form, where they reside, and how force or other signals regulate their behaviour to coordinate muscle growth and repair. Bone, heart and skin also respond to force by altered growth. Understanding the force detection and response systems in skeletal muscle is likely to illuminate the role of force in biology and regenerative medicine more generally.
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