Mechanisms of activity-dependent muscle growth and repair

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Muscle mass affects us throughout our lives. It is a major predictor of bone strength, sporting performance, career choice, propensity to obesity and diabetes and the development of debilitating muscle weakening in the elderly, which often leads to physical dependency. We know that people differ in muscle mass at birth due to genetic, epigenetic and environmental factors that impinge on mother and child during pregnancy. Although muscle grows hugely after birth, there is a strong correlation between muscle mass at birth and in later life. Muscle is made from several kinds of stem cells formed in the early embryo, yet how muscle mass is determined during prenatal life is unclear. This proposal aims to find out by understanding the fundamental cell and molecular biological processes that control the size of muscle tissue in a simple system. Skeletal muscle approaches 30-40% of human body mass, depending on sex and age. In addition to one's endowment at birth, physical activity during childhood and adolescence is thought to influence adult muscle mass, contractile properties and the balance between muscle and fat, which is a major predictor of healthspan. Measures of muscle/fat ratio correlate negatively with incidence of type 2 diabetes, coronary heart disease, stroke, colon, breast and other cancers, osteoarthritis, age-related muscle wasting and, of course, obesity. Although cause and effect are debated in these correlations, there is a consensus that a more 'athletic' physique (i.e. higher muscle/fat ratio) is likely to improve the health and outlook for a significant fraction of the population, with consequent economic and quality of life benefits for society as a whole. It is clear that 'environmental' effects, like exercise and food consumption, interact to control muscle mass, but they work on the tissue formed during earlier life. Emerging evidence indicates that exercise has long-term influences on whole body metabolism not just due to direct training effects on muscle itself, but also because exercised muscle releases signals that control growth of fat, heart and other tissues. There is thus a need to understand how muscle mass is controlled and is affected by physical activity. Our recent findings show that very early muscle tissue requires physical activity for normal growth and, within limits, has a remarkable ability to regulate its mass. We have also developed methods of watching the formation and growth of muscle from several distinct populations of stem cells in the living tissue. This proposal aims: 1) To understand the molecular mechanism(s) by which physical activity controls muscle growth. This study, while aimed at fundamental insight into development, will provide clues to the mechanisms by which training builds muscle in the elderly, athletes and for general health. By understanding how activity and the force it produces regulate muscle growth, the work will shed light on how force controls cell behaviour more generally.2) To discover how muscle tissue balances proliferation and differentiation of stem cells to control formation of the correct number of muscle fibres. By providing understanding of how muscle is built, these studies will reveal how our genes and early life experience interact to generate the muscular 'starting point', which, together with the vicissitudes of later life, controls general health and the onset of age-related diseases.3) To study how muscle tissue reacts to damage in early life and regenerates the correct amount of muscle. As muscle regeneration is important in athletes and fails in the late stages of many muscle diseases and in the elderly, this work may influence clinical practice by providing insight on how best to trigger appropriate muscle regeneration.