Download Statistics
Download StatisticsAllen, Sophie Louise (2022). Sarcopenia in chronic liver disease: novel mechanistic insights. University of Birmingham. Ph.D.
|
Allen2022PhD_Redacted.pdf
Text - Redacted Version Available under License All rights reserved. Download (23MB) | Preview |
Abstract
Sarcopenia, defined as the loss of muscle mass, quality and strength commonly occurs over the course of ageing and disease states such as chronic liver disease. In chronic liver disease sarcopenia is associated with a number of negative outcomes including an increase in mortality, increased risk of infections and an increase in length of hospital stay, presenting a major socioeconomic issue. Despite the known complications associated with the progression of sarcopenia, the mechanisms relating to its development across the different stages of chronic liver disease is largely unknown. Inflammatory cytokines and ammonia may be key systemic drivers of sarcopenia within cirrhosis. However, the investigation of these factors is limited to supraphysiological in vitro treatments. Therefore, in Chapter 3 we investigated the use of ex vivo human serum to condition C2C12 skeletal muscle cells in order to develop a more physiologically relevant model, which may be applied to a number of conditions to investigate the development of sarcopenia in both age and disease. We found that myotubes treated with serum from older individuals resulted in myotube atrophy and a blunted anabolic response to leucine provision. Based upon the in vitro model developed here, Chapter 4 assessed the potential mechanisms of myotube atrophy in C2C12s conditioned with serum from end-stage liver disease (ESLD), non-cirrhotic non-alcoholic fatty liver disease (NAFLD) patients and age-matched controls. We found a reduction in myotube diameter in cells treated with serum from ESLD patients, which may be characterised by a reduction in mitochondrial respiration, mitophagy and an increase in proteolysis. Following on from this in vitro work, in Chapter 5 we investigated fasted-state skeletal muscle regulatory protein content and gene expression in ESLD, NAFLD and age-matched controls. We found a decline in the protein content of OXPHOS complexes I and IV, alongside a decline in citrate synthase activity in ESLD patients. Additionally, we identified an upregulation in genes related to the oxidative stress response in ESLD and senescence in NAFLD patients. In conclusion, this thesis enhanced our understanding of the potential mechanisms which may underpin the development of sarcopenia in chronic liver disease, through the development of a novel in vitro model of liver disease and completion of an in vivo human muscle biopsy trial. These findings highlight that mitochondrial dysfunction may be a key driver of sarcopenia in ESLD. Additionally, we describe a valuable model for the investigation of nutritional and pharmaceutical compounds, prior to in vivo trials.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Award Type: | Doctorates > Ph.D. | |||||||||
| Supervisor(s): |
|
|||||||||
| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges (2008 onwards) > College of Life & Environmental Sciences | |||||||||
| School or Department: | School of Sport, Exercise and Rehabilitation Sciences | |||||||||
| Funders: | National Institute for Health Research | |||||||||
| Subjects: | Q Science > QP Physiology | |||||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/12461 |
Actions
 |
Request a Correction |
 |
View Item |
Downloads
Downloads per month over past year