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Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Department of Medicine, University of Wisconsin, Madison, Wisconsin.
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2013 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 12, 477-486 p.Article in journal (Refereed) Published
Abstract [en]

Critical illness myopathy (CIM) is characterized by a preferential loss of the motor protein myosin, muscle wasting, and impaired muscle function in critically ill intensive care unit (ICU) patients. CIM is associated with severe morbidity and mortality and has a significant negative socioeconomic effect. Neuromuscular blocking agents, corticosteroids, sepsis, mechanical ventilation, and immobilization have been implicated as important risk factors, but the causal relationship between CIM and the risk factors has not been established. A porcine ICU model has been used to determine the immediate molecular and cellular cascades that may contribute to the pathogenesis prior to myosin loss and extensive muscle wasting. Expression profiles have been compared between pigs exposed to the ICU interventions, i.e., mechanically ventilated, sedated, and immobilized for 5 days, with pigs exposed to critical illness interventions, i.e., neuromuscular blocking agents, corticosteroids, and induced sepsis in addition to the ICU interventions for 5 days. Impaired autophagy as well as impaired chaperone expression and protein synthesis were observed in the skeletal muscle in response to critical illness interventions. A novel finding in this study is impaired core autophagy machinery in response to critical illness interventions, which when in concert with downregulated chaperone expression and protein synthesis may collectively affect the proteostasis in skeletal muscle and may exacerbate the disease progression in CIM.

Place, publisher, year, edition, pages
2013. Vol. 45, no 12, 477-486 p.
Keyword [en]
intensive care unit; porcine ICU model; autophagy; chaperones; protein synthesis; skeletal muscle; critical illness myopathy and skeletal muscle proteostasis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-183955DOI: 10.1152/physiolgenomics.00141.2012ISI: 000320507100003OAI: oai:DiVA.org:uu-183955DiVA: diva2:565054
Available from: 2012-11-06 Created: 2012-11-06 Last updated: 2017-12-07Bibliographically 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. 63 p.
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)
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Supervisors
Available from: 2012-11-20 Created: 2012-11-06 Last updated: 2013-01-23Bibliographically approved

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Banduseela, VarunaGöransson Kultima, HannaAare, SudhakarLarsson, Lars

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