Muscle wasting in older adults
File(s)
Author(s)
Shrestha, Alvin
Type
Thesis or dissertation
Abstract
Sarcopenia is the age-related loss of skeletal muscle strength and function. It is associated with adverse events such as falls, dependence and mortality, with a financial burden amounting to billions of pounds. This thesis uses two studies to find predictors of muscle wasting. The Hip surgery study was designed to observe participants who would waste following elective hip surgery. It remained incomplete but showed feasibility through baseline measurements performed on those who were recruited. The LACE (Leucine and ACE inhibitors in sarcopenia) study was a randomised controlled trial using a sarcopenic cohort, which did not show ACE inhibitors or leucine to be effective in ameliorating sarcopenia. Blood samples from this study were used in this thesis to explore different predictors of muscle function.
Genetic influence on muscle function through polymorphisms of the bradykinin receptor 2 (BDKRB2) were tested. The TT genotype was associated with greater six-minute walk distance (6MWD) and higher muscle mass in men. Additionally in men, the +9+9 genotype was associated with greater arm fat mass.
Circulating levels of GDF-15 negatively correlated with 6MWD which was driven by men. Two polymorphisms of the GDF-15 loci known to be associated with GDF-15 levels were explored. For rs749451, participants with the CC genotype had significantly lower levels than the TT genotype. There were no differences in GDF-15 levels between rs1227731 genotypes, however the GG genotype had lower short physical performance battery scores in women.
Through Weighted Gene Co-expression Network Analysis, the blood transcriptome of the LACE cohort showed an association between erythropoiesis and loss of strength at 12 months. Immune response was associated negatively with future loss of strength at 12 months. The antimicrobial gene PGLYRP1 was successfully validated through quantitative PCR, where it correlated with gait speed, consistent with the findings using the R package DESeq2.
Genetic influence on muscle function through polymorphisms of the bradykinin receptor 2 (BDKRB2) were tested. The TT genotype was associated with greater six-minute walk distance (6MWD) and higher muscle mass in men. Additionally in men, the +9+9 genotype was associated with greater arm fat mass.
Circulating levels of GDF-15 negatively correlated with 6MWD which was driven by men. Two polymorphisms of the GDF-15 loci known to be associated with GDF-15 levels were explored. For rs749451, participants with the CC genotype had significantly lower levels than the TT genotype. There were no differences in GDF-15 levels between rs1227731 genotypes, however the GG genotype had lower short physical performance battery scores in women.
Through Weighted Gene Co-expression Network Analysis, the blood transcriptome of the LACE cohort showed an association between erythropoiesis and loss of strength at 12 months. Immune response was associated negatively with future loss of strength at 12 months. The antimicrobial gene PGLYRP1 was successfully validated through quantitative PCR, where it correlated with gait speed, consistent with the findings using the R package DESeq2.
Version
Open Access
Date Issued
2025-09-12
Date Awarded
2026-06-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Fertleman, Michael
Bull, Anthony
Publisher Department
Department of Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)