Sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease affecting adults over the age of 50. Although the aetiology of this disease remains unclear, there is evidence for both inflammatory and myodegenerative processes in sIBM muscle pathology. In particular, abnormal protein aggregation is characteristic of affected muscle, with inclusion bodies incorporating amyloid-beta precursor protein (β-APP) among many others. Therapeutic interventions tested to date for sIBM have targeted the immune system; but none have been beneficial and sIBM currently remains untreatable. In this study, an in vitro model of the degenerative pathology seen in sIBM was established by over-expressing β-APP in primary muscle cultures. This resulted in the formation of inclusion bodies immuno-reactive for β-APP and other sIBM-relevant proteins, as well as increased cytotoxicity, proteasome dysfunction, mitochondrial abnormalities and TDP-43 mis-localisation; all observed in sIBM patient muscle. The heat shock response (HSR) is an acute endogenous cytoprotective mechanism that responds to misfolded proteins. Up-regulation of the HSR was examined by treatment with Arimoclomol, a co-inducer of the HSR, which showed beneficial effects in this in vitro model of IBM by significantly improving cell survival and attenuating cellular pathology. Since proteasome dysfunction has been implicated in sIBM pathology, I also examined the effects of pharmacological inhibition of the proteasome on muscle cells in culture. Proteasome inhibition did not result in the appearance of several key features of sIBM, suggesting that this is not a suitable approach to modeling sIBM. However, treatment with Arimoclomol was seen to significantly improve proteasome function and cell survival in these experiments. Using the β-APP model, eight novel pharmacological agents, with known anti-aggregation properties, were subsequently screened and one agent was found to significantly ameliorate the disease outcomes established in this model. The results of this Thesis show that β-APP over-expression in vitro recapitulates many of the characteristic features of sIBM and can be used successfully to screen potential therapies. In particular, Arimoclomol and one novel agent have been identified as potential therapeutic agents for IBM.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:565816 |
| Date | January 2012 |
| Creators | Ahmed, M. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1343623/ |
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