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The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
Department of anesthesiology, Karolinska Inistitute.
Department of anesthesiology, Karolinska Inistitute.
Research center for genetic medicine. (children national medical center washington)
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2012 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 18, 865-877 p.Article in journal (Refereed) Published
Abstract [en]

Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.

Place, publisher, year, edition, pages
2012. Vol. 44, no 18, 865-877 p.
Keyword [en]
Sepsis, porcine, muscle wasting, intensive care
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-180380DOI: 10.1152/physiolgenomics.00031.2012ISI: 000309109100001OAI: oai:DiVA.org:uu-180380DiVA: diva2:549807
Available from: 2012-09-05 Created: 2012-09-05 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms
Open this publication in new window or tab >>Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors.

The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 812
Keyword
acute quadriplegic myopathy, gene expression, myosin, heat shock proteins, mechanical ventilation, myostatin, sepsis, corticosteroids, diaphragm
National Category
Medical and Health Sciences Neurosciences
Research subject
Clinical Neurophysiology
Identifiers
urn:nbn:se:uu:diva-180374 (URN)978-91-554-8469-9 (ISBN)
Public defence
2012-10-24, Hedstrandsalen, Ingang 70, bv Akademiska Sukhuset, Uppsala, 13:15 (English)
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Available from: 2012-10-03 Created: 2012-09-05 Last updated: 2013-01-23Bibliographically approved

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Aare, SudhakarLarsson, Lars

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