The role of p38 MAPK in the adult muscle stem cell fate and regeneration in ageing

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In part due to advances in modern medicine, many of us are living longer, and a greater proportion of the population of the Western world is over 60 than ever before. However, there is reduced benefit to these extra years of life if they are overshadowed by poor health; we want to increase 'healthspan' not 'lifespan'. What determines healthy ageing? What does it mean to die 'of old age' rather than some disease? We do not understand these processes yet. One strong candidate for the maintenance and repair of the body is a specialized cell called the adult stem cell. These differ from the embryonic stem cells that are so often in the press. Whereas embryonic stem cells have the ability to differentiate into any lineage (and become any tissue), the adult stem cell is committed to repairing and regenerating the tissue in which it resides. It achieves this by i, activating in response to cues, such as injury ii, proliferating, providing a pool of cells that will repair the damage and iii, through one of these cell divisions, replacing itself for future use. In the elderly, the ability of adult stem cells to perform these functions in markedly reduced, leading to gradual tissue deterioration. A good exemplar of this is skeletal muscle. After the age of 50, skeletal muscle mass declines by ~10% per decade; muscle also becomes weaker and contains more fat. On the positive side, studies in animals have determined that the decline in muscle adult stem cell (called the 'satellite' cell) behavior in ageing is not due to defects within the cell itself but is rather because the cell does not receive the correct signals from its environment. The overall aim of this project is to examine the theory that a key signaling molecule, called p38 MAPK, has a key role in interpreting these signals from the environment and dictating the way in which satellite cells subsequently behave; it therefore acts as a 'gateway'. p38 regulates many of the important events in muscle satellite cell activation, ranging from stopping cells dividing to changing the genes that are activated and therefore the proteins that the cell can make. If p38 is activated too soon, adult stem cells will not have sufficient opportunity to form enough cells for repair and replacement. We will address the following specific questions: 1) Does increased p38 activity restrict the 'choices' of muscle satellite cells? What would happen if p38 activity were suppressed? We will answer this by generating mice that lack p38 in adult muscle stem cells (knockout mice). We expect that they may produce increased numbers of precursor cells. 2) What are the first stages by which p38 regulates gene expression? DNA does not exist as a naked strand but is rather wound around groups of proteins called histones (the whole unit is called chromatin). Histones can be modified by the addition of methyl groups; it is now believed that these modifications ultimately change the shape of chromatin, either making it compact and inaccessible to molecules that will encourage gene expression (transcription factors), or 'opening' the chromatin so that transcription factors can function. We will examine two fundamental histone modifications, which regulate each of these events. 3) What are the signals that control p38 activation? Some of these will come from outside the cell, and some from inside. We will increase or decrease the activity of candidate regulators and determine the consequences for p38 activity and satellite cell function. 4) Most important, what changes occur in p38 activity during ageing? What happens if we prevent p38 activation in muscle satellite cells from old animals? We will test this using the knockout mice made in point 1. We predict that the normal decrease in satellite cell activation and proliferation that occurs in old mice will be ameliorated in the p38 knockout mice. This may prevent part of the decline in muscle mass that occurs in ageing.