Molecular changes underlying maturation and adaptation of the neuromuscular synapse.
Muscle weakness is an important cause of elderly people loosing their personal independence. This project will investigate the potential of the agrin/MuSK/rapsyn signalling system in muscle to help sustain nerve control of muscle in old age.
From about 60 years of age the motor system goes into decline. There are declines in the number of connections between motor neurons and muscle fibres and in muscle mass and strength (sarcopenia). This is an important contributing cause to the loss of independence in the growing numbers of elderly people. It now seems likely that failure of the connection between nerve and muscle, the neuromuscular junction (NMJ) occurs late in life causing at least part of this weakness. Mice have a lifespan of 2-3 years and our recent work has determined the time-course for the loss of neuromuscular connections in mice with age. We also found that mice permitted voluntary running exercise from middle age onward retained larger NMJs in old age. This leads to the critical question of the factors and mechanisms that sustain neuromuscular connections. The agrin-MuSK-rapsyn system is important for the development of nerve-muscle connections during embryonic development. There is also reason to suspect that this system remains important for maintaining the neuromuscular junction (NMJ) later in life. The first aim of the project will be to test how dependent the aging NMJ is to the signalling function of the agrin-MuSK-rapsyn system. We will use quantitative immunofluorescence and confocal microscopy to compare the size and structure of the NMJ in aging wild-type mice with NMJs of mice that have only one copy of either the agrin, MuSK or rapsyn gene (heterozygote mice). We predict that if any of these pathway genes play a limiting role in NMJ maintenance and regeneration then halving the expression of them will result in, fewer and smaller NMJs. If extended to a PhD we will then test whether we can improve the structure and function of NMJs in aging mice by increasing the level of expression of MuSK pathway proteins in the muscle of aging mice and by enhancing the MuSK signalling activity in other ways.
This co-supervisor for this project is Associate Professor Peter Noakes from the University of Queensland
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The opportunity ID for this research opportunity is: 16
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