U489173.pdf (4.23 MB)
Regulation of metabolic acidosis-induced skeletal muscle wasting
thesisposted on 2014-12-15, 10:40 authored by Warren Paul Pickering
This work aims to investigate metabolic acidosis induced skeletal muscle protein wasting, and the inter-relationships between: metabolic acidosis, glucocorticoids (GC), and the ubiquitin proteasome system in this process.;Experiments were undertaken using three key themes and models: 1. The role of glucocorticoids and apoptosis in the process of protein degradation (PD) in L6G8C5 myoblasts in a cell culture system of metabolic acidosis utilizing dexamethasone and the glucocorticoid antagonist RU38486. Stimulation of PD in these cells by acid and GC does not appear to be an artefact of apoptosis or dedifferentiation, but differentiation state does determine whether PD responds spontaneously to acid or (as in vivo) only does so in the presence of GC. 2. The ability of RU38486 to pharmacologically antagonize the suggested permissive effect of glucocorticoid in an in vivo model of acidosis-induced muscle wasting. RU38486 did not prevent the acidosis-induced muscle wasting in this model despite demonstration of significant GC receptor blockade. 3. The role of the ATP-dependent ubiquitin proteasome system in the malnutrition of patients treated by peritoneal dialysis. When serum bicarbonate increased in these patients weight and body mass index increased significantly as did plasma BCAA. Muscle levels of ubiquitin mRNA decreased significantly; serum tumour necrosis factor-a also decreased. These results indicate that even a small correction of serum bicarbonate improves nutritional status, and provide evidence for down-regulation of BCAA degradation and muscle proteolysis via the ubiquitin proteasome system. Whether acidosis and inflammatory cytokines (such as TNF-alpha) interact to impair nutrition remains to be determined.
Date of award2005-01-01
Author affiliationInfection immunity and inflammation
Awarding institutionUniversity of Leicester