Role of mRNA localisation and translational control in muscle growth

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Skeletal muscle makes up 40% of our body mass and its maintenance is essential for a good quality of life. In various diseases and particularly in older or hospitalised people, muscle wasting is a serious problem. The physical activity of exercise prevents wasting and increases 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 activity and responds by growing. In the past, we have discovered that early muscle develops similarly in fish, mice and people. Such early muscle development generally involves a fixed programme controlled by our genes. Now, we want to study the role of activity in regulating how genes control later muscle growth. For genes to function, their DNA sequence must be 'translated' into an amino acid sequence, thereby forming the proteins that build the body. The cellular machinery that carries out translation uses a copy of the gene DNA, known as messenger RNA (mRNA) as a template for protein synthesis. We have discovered that certain mRNAs are localised to the ends of muscle fibres. The activity of muscle contraction regulates how rapidly proteins are made from these localised mRNAs, thereby controlling muscle growth and function. We have discovered that a protein called BP3L controls translation of some of these mRNAs. So our first aim is determine the role of BP3L in normal muscle growth in response to activity. We will use zebrafish embryos and larvae 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 which genes control growth, c) small and accessible, so we can easily control activity of the living muscle. These things are more difficult to do in mammals. Our second aim is to discover the full array of mRNAs regulated by BP3L by using a combination of traditional biochemistry and new genomics methods. This will give us the 'big picture' from which we will use our long experience of muscle biology to focus on specific mRNAs controlling muscle growth and function of mRNAs located at fibre ends. Both BP3L and its known targets are located at muscle fibre ends. These 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 activity-detectors that initiate the process of growth in response to certain kinds of contractile activity. So our third aim is to understand how muscle activity regulates BP3L and thereby coordinates muscle growth. As in muscle, translation of localised mRNA in nerve cells is regulated by activity during learning and memory. So our findings may have a broader application. Moreover, one possible hypothesis that we will test is that the physical force produced by activity regulates mRNA translation. Elucidating such a mechanism would have importance throughout biology, as cells in plants and animals respond to physical forces that control their growth, for example in skin callousing or the growth of windswept trees. Understanding the force detection and response systems in skeletal muscle is likely to illuminate the role of force in biology and medicine.