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Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
Department of anesthesiology, Karolinska Inistitute.
Department of anesthesiology, Karolinska Inistitute.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
Vise andre og tillknytning
2013 (engelsk)Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, nr 8, s. 312-320Artikkel i tidsskrift (Fagfellevurdert) 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.

 

sted, utgiver, år, opplag, sider
2013. Vol. 45, nr 8, s. 312-320
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-180375DOI: 10.1152/physiolgenomics.00123.2012ISI: 000317662000002PubMedID: 23429211OAI: oai:DiVA.org:uu-180375DiVA, id: diva2:549789
Tilgjengelig fra: 2012-09-05 Laget: 2012-09-05 Sist oppdatert: 2017-12-07bibliografisk kontrollert
Inngår i avhandling
1. Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms
Åpne denne publikasjonen i ny fane eller vindu >>Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2012. s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 812
Emneord
acute quadriplegic myopathy, gene expression, myosin, heat shock proteins, mechanical ventilation, myostatin, sepsis, corticosteroids, diaphragm
HSV kategori
Forskningsprogram
Klinisk neurofysiologi
Identifikatorer
urn:nbn:se:uu:diva-180374 (URN)978-91-554-8469-9 (ISBN)
Disputas
2012-10-24, Hedstrandsalen, Ingang 70, bv Akademiska Sukhuset, Uppsala, 13:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2012-10-03 Laget: 2012-09-05 Sist oppdatert: 2018-01-12bibliografisk kontrollert

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