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Impact of post-synaptic block of neuromuscular transmission, muscle unloading and mechanical ventilation on skeletal muscle protein and mRNA expression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
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2006 (English)In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 453, no 1, 53-66 p.Article in journal (Refereed) Published
Abstract [en]

To analyse mechanisms of muscle wasting in intensive care unit patients, we developed an experimental model where rats were pharmacologically paralysed by post-synaptic block of neuromuscular transmission (NMB) and mechanically ventilated for 9 2 days. Specific interest was focused on the effects on protein and mRNA expression of sarcomeric proteins, i.e., myosin heavy chain (MyHC), actin, myosin-binding protein C (MyBP-C) and myosin-binding protein H (MyBP-H) in fast- and slow-twitch limb, respiratory and masticatory muscles. Muscle-specific differences were observed in response to NMB at both the protein and mRNA levels. At the protein level, a decreased MyHC-to-actin ratio was observed in all muscles excluding the diaphragm, whereas at the mRNA level a decreased expression of the dominating MyHC isoform(s) was observed in the hind limb and intercostal muscles, but not in the diaphragm and masseter muscles. MyBP-C mRNA expression was decreased in the limb muscles, but it otherwise remained unaffected. MyBP-H conversely increased in all muscles. Furthermore, we found myofibrillar protein and mRNA expression to be affected differently when comparing NMB; animals with peripherally denervated (DEN) ambulatory rats. We report that NMB; has both a larger and different impact on muscle, at the protein and mRNA levels, than DEN has.

Place, publisher, year, edition, pages
2006. Vol. 453, no 1, 53-66 p.
Keyword [en]
myosin, actin, neuromuscular blockade, immobilisation, mechanical ventilation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94833DOI: 10.1007/s00424-006-0110-5ISI: 000242343400006PubMedID: 16868767OAI: oai:DiVA.org:uu-94833DiVA: diva2:168828
Available from: 2006-09-18 Created: 2006-09-18 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Cellular and Molecular Mechanisms Underlying Acute Quadriplegic Myopathy: Studies in Experimental Animal Models and Intensive Care Unit Patients
Open this publication in new window or tab >>Cellular and Molecular Mechanisms Underlying Acute Quadriplegic Myopathy: Studies in Experimental Animal Models and Intensive Care Unit Patients
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 171
Keyword
Neurosciences, Acute Quadriplegic Myopathy, intensive care unit, atrophy, myosin heavy chain, actin, myosin binding proteins, nuclear transcription factors, mRNA, Neurovetenskap
Identifiers
urn:nbn:se:uu:diva-7133 (URN)91-554-6646-X (ISBN)
Public defence
2006-10-10, Enghoffsalen, University Hospital, Akademiska Sjukhuset, Ing 50, Uppsala, 09:00
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Available from: 2006-09-18 Created: 2006-09-18Bibliographically approved

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