Role of motor unit remodelling in age-related loss of skeletal muscle fibres.

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As we age our muscles become smaller and weaker and the reduced muscle function eventually contributes to frailty and poor quality of life. These changes occur partly because we lose a large proportion of the muscle cells (called muscle fibres), but also the muscle that we retain is weak. It is currently unknown how muscle fibres are lost during ageing, but when these fibres die, the motor nerves that normally control their activity are also lost. A fundamental question that has not yet been answered is whether the processes of ageing lead to a loss of proper functioning of nerves that causes loss of the muscle fibres activated by the nerve, or vice versa - that the primary changes in ageing are a loss of muscle that then causes loss of the nerve. This is a crucially important point since effective interventions to preserve muscle, or reverse the age-related changes in muscle function, will need to be targeted at the primary site of changes to be effective.We believe that, as we age, the way that nerves respond to damage changes such that eventually they become very slow to respond to everyday trauma experienced during activity and this leads to degeneration of the muscle fibres that the specific nerve branch supplies. Understanding whether the muscle fibres supplied by damaged nerve branches show the initial degenerative changes in ageing that eventually leads to loss of muscle fibres is crucial to finding ways of preventing muscle loss in ageing. Microscopes that detect very sensitive changes in nerve and muscle tissue have been developed that now allow us to examine the chronological changes that occur with ageing in individual motor nerves and the muscle fibres that they activate. This approach will be used to examine individual nerves and muscle of ageing mice, since these animals show a similar pattern of ageing and weakness to humans. The project will therefore use this form of microscopy (intra vital confocal microscopy) to determine whether all of the muscle fibres from old mice show age-related changes in several degenerative pathways, or whether only fibres where the specific nerve branch is disrupted show these changes. Data from this study should determine whether degeneration of the nerve is likely to be the key initial change during ageing. Finally we will undertake a study to attempt to identify factors that are released from muscle of young mice that stimulate rapid re-growth of nerve branches when these are damaged. Such substances are likely to be missing or modified in muscles from old mice, but replacement of them may potentially provide a means of helping preserve muscle during ageing.Completion of these studies will provide crucial information on the mechanisms underlying muscle weakness during ageing and provide indicators of the type of therapeutic interventions that may help preserve peripheral nerve and muscle function during ageing.