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Effects of corticosteroids 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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
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2013 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 8, 312-320 p.Article in journal (Refereed) Published
Abstract [en]

Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator and a decreased quality of life post-ICU. The mechanisms underlying limbmuscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization and systemic administration of corticosteroids (CS).  These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for five days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes using microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional up-regulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response , cytoskeletal, sarcomeric and heat shock protein as well as protein synthesis at the translational level appear to play an additive deleterious role for the  limb muscle weakness in immobilized ICU patients.

 

Place, publisher, year, edition, pages
2013. Vol. 45, no 8, 312-320 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-180375DOI: 10.1152/physiolgenomics.00123.2012ISI: 000317662000002PubMedID: 23429211OAI: oai:DiVA.org:uu-180375DiVA: diva2:549789
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, SudhakarAkkad, HazemLars, Larsson

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