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The genetics of sarcopenia and skeletal muscle phenotypes in elderly Caucasian women

Khanal, Praval (2018) The genetics of sarcopenia and skeletal muscle phenotypes in elderly Caucasian women. Doctoral thesis (PhD), Manchester Metropolitan University in collaboration with Katholieke Universiteit Leuven.

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Abstract

It is well documented that there is a loss of muscle mass and muscle strength with ageing, often termed sarcopenia. There remains inconsistency in identifying a definition of sarcopenia that can 1) provide a meaningful discrimination between non-sarcopenic and sarcopenic groups for muscle phenotypes, and 2) identify a sarcopenic population of sufficient numbers for subsequent genetic analysis. Of the factors that determine the prevalence of sarcopenia and the severity of impairments in muscle phenotypes, genetics remains unreported other than for a few single nucleotide polymorphisms (SNPs, e.g. VDR, ACTN3 and IL-6). The aims of the present thesis were, in the first instance, to identify a meaningful definition of sarcopenia in a Caucasian elderly female population (n =307, 60-91 years), and thereafter to investigate the possible association of multiple SNPs (n=24) with sarcopenia and muscle phenotypes, and subsequently to assess the polygenic profile of muscle phenotypes in elderly women. A novel definition of sarcopenia was identified based on a Z-score approach using handgrip strength and skeletal muscle mass index. Thereafter, a novel association of HIF1A rs11549465 CC and ACE rs4341 CC as risk genotypes for sarcopenia was identified. Subsequently, skeletal muscle phenotypes differentiated by sarcopenia were assessed for further association with SNPs. In doing so, 12 out of 24 polymorphisms were identified as having an association with one or more of the investigated skeletal muscle phenotypes (e.g PTK2, HIF1A & ACVR1B). Adopting the polygenic data driven approach (GPSdd), up to 8.2% and 5.0% of the variance of skeletal muscle size and strength were accounted for, this increased to 14.5% and 17.2% when age was included in the model. In conclusion, there appears to be a genetic influence on sarcopenia and skeletal muscle phenotypes; with novel skeletal muscle associations reported. The findings of this thesis have applications in a variety of areas, particularly within ageing populations, for whom completion of activities of daily living may be improved because of better understanding their individual-specific muscle mechanics, and genetic risk for physical impairment.

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