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Genetic and DNA methylation markers of ageing muscle

Lingxiao HE (2020) Genetic and DNA methylation markers of ageing muscle. Doctoral thesis (PhD), Manchester Metropolitan University in collaboration with Katholieke Universiteit Leuven.

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Abstract

Inter-individual variation can be found in muscle mass and strength during the ageing process, and in muscular adaptations to exercise. These inter-individual differences are related to genetic and DNA methylation factors. Therefore, the objective of this thesis is to explore the role of underlying genetic polymorphisms and DNA methylation with muscle strength and mass in an ageing population. This thesis first evaluated the overall genetic association with changes in muscle mass and strength among older adults (n = 200, 60–83 yrs) who received a one year of training and were reassessed one year after the cessation of training. The genetic profile was represented as a data-driven genetic predisposition score (GPS), which was calculated based on muscle-related genetic variants selected from 170 candidates through stepwise regression. The results showed that a data-driven GPS explained 0.7% of the variance in skeletal muscle mass (SMM) and 3.2% of the variance in knee strength at baseline level, 14% of the variance in SMM and 27% of the variance in knee strength after the training, and 27–37% of the variance in the loss of muscle mass and strength after the one-year cessation of training. The thesis further compared differences in blood sample methylation patterns between sarcopenic and non-sarcopenic women (n = 48, 65–80 yrs). 6,258 differentially methylated CpGs (dmCpGs) that had different methylation levels (p < 0.01) between the sarcopenic and non-sarcopenic groups were identified. Genes containing these dmCpGs were involved in multiple biological pathways that were related to muscle function, actin cytoskeleton regulation and energy metabolism. A DNA methylation profile score was calculated as a weighted sum of methylation levels of sarcopeniadriven CpG sites (MSSAR, based on sarcopenia-related lasso logistic regression) and the MSSAR was negatively associated with vastus lateralis size, elbow and knee strength, and explained 10.1%, 35.5% and 40.1% of the variance, respectively. In conclusion, this thesis shows that both genetic sequence architecture and DNA methylation play a role in explaining the inter-individual differences in muscle mass and strength in older adults. An individual with a more favourable genetic profile might have not only greater baseline muscle strength, but also a higher probability to respond well to training and a smaller muscular loss after quitting the training. This study provided new insights in how the methylation status differ between weak older women compared to generally age-matched muscularly fit women. Using easily accessible blood samples, individuals at high risk of sarcopenia might be identified based on their methylation profile.

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