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Gene expression and muscle fiber function in a porcine ICU model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (neurofysiologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (neurofysiologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Cancer Pharmacology and Informatics)
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2009 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 39, no 3, p. 141-159Article in journal (Refereed) Published
Abstract [en]

Skeletal muscle wasting and impaired muscle function in response to mechanical ventilation and immobilization in intensive care unit (ICU) patients are clinically challenging partly due to 1) the poorly understood intricate cellular and molecular networks and 2) the unavailability of an animal model mimicking this condition. By employing a unique porcine model mimicking the conditions in the ICU with long-term mechanical ventilation and immobilization, we have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a 5-day period. Among the differentially regulated transcripts, extracellular matrix, energy metabolism, sarcomeric and LIM protein mRNA levels were downregulated, while ubiquitin proteasome system, cathepsins, oxidative stress responsive genes and heat shock proteins (HSP) mRNAs were upregulated. Despite 5 days of immobilization and mechanical ventilation single muscle fiber cross-sectional areas as well as the maximum force generating capacity at the single muscle fiber level were preserved. It is proposed that HSP induction in skeletal muscle is an inherent, primary, but temporary protective mechanism against protein degradation. To our knowledge, this is the first study that isolates the effect of immobilization and mechanical ventilation in an ICU condition from various other cofactors.

Place, publisher, year, edition, pages
American Physiological Society , 2009. Vol. 39, no 3, p. 141-159
Keyword [en]
Mechanical ventilation, immobilization, muscle function, gene expression, ubiquitin proteasome system, heat shock proteins, Lim proteins, intensive care unit
National Category
Neurosciences
Research subject
Clinical Neurophysiology
Identifiers
URN: urn:nbn:se:uu:diva-120652DOI: 10.1152/physiolgenomics.00026.2009ISI: 000271525900002PubMedID: 19706692OAI: oai:DiVA.org:uu-120652DiVA, id: diva2:303794
Available from: 2010-03-15 Created: 2010-03-15 Last updated: 2018-01-12Bibliographically approved
In thesis
1. Molecular And Cellular Networks in Critical Illness Associated Muscle Weakness: Skeletal Muscle Proteostasis in the Intensive Care Unit
Open this publication in new window or tab >>Molecular And Cellular Networks in Critical Illness Associated Muscle Weakness: Skeletal Muscle Proteostasis in the Intensive Care Unit
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Critical illness associated muscle weakness and muscle dysfunction in intensive care unit (ICU) patients lead to severe morbidity and mortality as well as significant adverse effect on quality of life. Immobilization, mechanical ventilation, neuromuscular blocking agents, corticosteroids, and sepsis have been implicated as important risk factors, but the underlying molecular and cellular mechanisms remain unclear.  A unique porcine ICU model was employed to investigate the effect of these risk factors on the expression profiles, gene expression and contractile properties of limb and diaphragm muscle, in the early phase of ICU stay. This project has focused on unraveling the underlying molecular and cellular pathways or networks in response to ICU and critical illness interventions.

Upregulation of heat shock proteins indicated to play a protective role despite number of differentially transcribed gene groups that would otherwise have a negative effect on muscle fiber structure and function in response to immobilization and mechanical ventilation.  Mechanical ventilation appears to play a critical role in development of diaphragmatic dysfunction. Impaired autophagy, chaperone expression and protein synthesis are indicated to play a pivotal role in exacerbating muscle weakness in response to the combined effect of risk factors in ICU. These results may be of therapeutic importance in alleviating critical illness associated muscle weakness.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. p. 63
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 841
Keyword
chaperones, autophagy, intensive care unit, heat shock proteins, protein synthesis, proteostasis, ER stress, gene expression, sepsis, neuromuscular blockers, corticosteroids, immobilisation, mechanical ventilation
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Molecular Cellbiology; Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-183959 (URN)978-91-554-8542-9 (ISBN)
Public defence
2012-12-11, B7:113, BMC, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-11-20 Created: 2012-11-06 Last updated: 2013-01-23Bibliographically approved

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Banduseela, Varuna C.Ochala, JulienGöransson, HannaLarsson, Lars

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