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Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
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 Neuroscience, Clinical Neurophysiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
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2011 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, no 24, 1334-1350 p.Article in journal (Refereed) Published
Abstract [en]

Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.

Place, publisher, year, edition, pages
2011. Vol. 43, no 24, 1334-1350 p.
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-164317DOI: 10.1152/physiolgenomics.00116.2011ISI: 000298403600002PubMedID: 22010006OAI: oai:DiVA.org:uu-164317DiVA: diva2:467318
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically 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, SudhakarOchala, JulienGöransson, HannaLarsson, Lars

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