Skeletal muscles are involved in numerous processes including postural maintenance, locomotion, ventilation of lungs and protection of the bones and viscera. Muscle also plays important roles in chronic diseases including sarcopenia, cachexia, insulin resistance and diabetes. The major component of muscle is the constituent muscle fibres. Muscle fibre cross-sectional area (CSA), fibre number, and proportion of fibre types are important determinants of muscle function, overall metabolism and the quality and quantity of meat in livestock. Genetic variation plays a substantial role in the variation observed in fibre traits. The underlying pathways and genes remain poorly understood; therefore a greater understanding can potentially lead to treatments of disease. The aim of this thesis was to gain a deeper understanding of the genetic mechanisms which underlie variation in the number, CSA and type of muscle fibres. Linkage analysis of soleus fibre properties was performed in an F2 intercross, and refined in the F34 intercross of two strains selected for high and low bodyweight, LG/J and SM/J respectively. Quantitative trait loci (QTL) were then integrated with LG/J and SM/J muscle transcriptome data to identify candidate genes. Genome-wide association analysis identified 6 QTL affecting properties of muscle fibres. Transcriptome analysis indicated a number of differentially expressed candidate genes within the QTL; Ppp1r16b, Gm826, Chd6, Alad, Akap2, E130308A19Rik, Gm9174 and Hdhd3. Functional testing of a mouse Chd6 knockout 5 model confirmed no involvement in fibre properties and has therefore been discounted from the candidate genes. The genetic mechanisms accounting for the differing fibre properties in the LG/J and SM/J strains have been elucidated in greater detail. Integration of QTL mapping and transcriptome data led to a manageable number of candidate genes which could underlie the effects of the QTL via differential expression or coding sequence differences. Available knockout models will facilitate validation of the candidate genes.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:600086 |
| Date | January 2013 |
| Creators | Carroll, Andrew Mark |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=206601 |
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