Somitic muscle growth: a new model for the role of force in morphogenesis

点击翻译按钮获取中文摘要

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.