The combination of a severe systemic illness, corticosteroids, and neuromuscular blocking agents in patients on the mechanical ventilator often results in a condition known as Acute Quadriplegic Myopathy (AQM). While severe weakness of all spinal nerve innervated muscles is known to be a significant clinical characteristic of the disease, this symptom is typically not recognized until the disease has progressed to an advanced stage. End result effects have been classified, which include the loss of the thick filament, or myosin heavy chain, an in-excitable muscle membrane, and an up-regulation of protein degradation; however, there is little known about the acute stage of AQM. This project has focused on understanding the underlying mechanisms of AQM, specifically in regard to protein synthesis, both at the mRNA and nuclear transcription levels. To study the early stages of the disease two animal models have been developed: rat and pig. Further, we have examined AQM muscle tissue, to investigate the similarities of our animal models to patients, as well as to study the recovery process. Particular interest was directed on the myofibrillar proteins myosin (MyHC) and actin, as they are the primary proteins involved in muscle contraction, as well as the myosin associated proteins, myosin binding protein C and H. At the mRNA level, MyHC and actin are both down-regulated in response to AQM. The myosin binding proteins are affected differently, with H protein increasing during severe atrophy and C protein either being slightly down-regulated or unchanged. Nuclear transcription factors were also affected, with such factors as MuRF1 and MAFbx up-regulated. Thus far results have shown that protein synthesis is altered in AQM and largely contributes to both the development and recovery of the disease. The pathways of protein synthesis may prove to be an ideal target for the prevention of AQM and/or symptom alleviation.
| Identifer | oai:union.ndltd.org:UPSALLA1/oai:DiVA.org:uu-7133 |
| Date | January 2006 |
| Creators | Norman, Holly |
| Publisher | Uppsala universitet, Institutionen för neurovetenskap, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, info:eu-repo/semantics/doctoralThesis, text |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 171 |
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