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Time-course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
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2014 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 592, no 17, 3859-3880 p.Article in journal (Refereed) Published
Abstract [en]

Controlled mechanical ventilation (CMV) plays a key role in triggering the impaired diaphragm muscle function and the concomitant delayed weaning from the respirator in critically ill intensive care unit (ICU) patients. To date, experimental and clinical studies have primarily focused on early effects on the diaphragm by CMV, or at specific time points. To improve our understanding of the mechanisms underlying the impaired diaphragm muscle function in response to mechanical ventilation, we have performed time‐resolved analyses between 6 h and 14 days using an experimental rat ICU model allowing detailed studies of the diaphragm in response to long‐term CMV. A rapid and early decline in maximum muscle fibre force and preceding muscle fibre atrophy was observed in the diaphragm in response to CMV, resulting in an 85% reduction in residual diaphragm fibre function after 9–14 days of CMV. A modest loss of contractile proteins was observed and linked to an early activation of the ubiquitin proteasome pathway, myosin:actin ratios were not affected and the transcriptional regulation of myosin isoforms did not show any dramatic changes during the observation period. Furthermore, small angle X‐ray diffraction analyses demonstrate that myosin can bind to actin in an ATP‐dependent manner even after 9–14 days of exposure to CMV. Thus, quantitative changes in muscle fibre size and contractile proteins are not the dominating factors underlying the dramatic decline in diaphragm muscle function in response to CMV, in contrast to earlier observations in limb muscles. The observed early loss of subsarcolemmal neuronal nitric oxide synthase activity, onset of oxidative stress, intracellular lipid accumulation and post‐translational protein modifications strongly argue for significant qualitative changes in contractile proteins causing the severely impaired residual function in diaphragm fibres after long‐term mechanical ventilation. For the first time, the present study demonstrates novel changes in the diaphragm structure/function and underlying mechanisms at the gene, protein and cellular levels in response to CMV at a high temporal resolution ranging from 6 h to 14 days.

Place, publisher, year, edition, pages
2014. Vol. 592, no 17, 3859-3880 p.
National Category
Physiology Neurology
Identifiers
URN: urn:nbn:se:uu:diva-192529DOI: 10.1113/jphysiol.2014.277962ISI: 000341771400013OAI: oai:DiVA.org:uu-192529DiVA: diva2:599850
Funder
Swedish Research Council, 8651, 4423
Available from: 2013-01-22 Created: 2013-01-22 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Intensive care Muscle Wasting and Weakness: Underlying Mechanisms, Muscle Specific Differences and a Specific Intervention Strategy
Open this publication in new window or tab >>Intensive care Muscle Wasting and Weakness: Underlying Mechanisms, Muscle Specific Differences and a Specific Intervention Strategy
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The intensive care unit (ICU) condition, i.e., immobilisation, sedation and mechanical ventilation, often results in severe muscle wasting and weakness as well as a specific acquired myopathy, i.e., Acute Quadriplegic Myopathy (AQM). The exact mechanisms underlying AQM remain incomplete, but this myopathy is characterised a preferential myosin loss and a decreased muscle membrane leading to a delayed recovery from the primary disease, increased mortality and morbidity and altered quality of life of survivors. This project aims at improving our understanding of the mechanisms underlying the muscle wasting and weakness associated with AQM and explore the effects of a specific intervention strategy. Time-resolved analyses have been undertaken using a unique experimental rodent ICU model and specifically studying the muscle wasting and weakness in limb and diaphragm muscles over a two week period. Further, we used passive mechanical loading in an attempt to alleviate the impaired muscle function and wasting associated with the ICU condition. Subsequently, the knowledge gained from the animal model was translated into a clinical study. Mechanical silencing (absence of external and internal strain) due to immobilisation, pharmacological neuromuscular blockade and sedation, was identified as a key factor triggering the muscle wasting and weakness associated with AQM in limb muscles. In addition, MuRF1, a member of the ubiquitin proteasome degradation pathway is playing a major role in the contractile protein degradation observed in both the diaphragm and limb muscles offering a potential candidate for future therapeutic approaches. Moreover, passive mechanical loading resulted in significant positive effects on muscle structure and function in the rodent ICU model, decreasing muscle atrophy and the loss of force generating capacity. In ICU patients passive mechanical loading improved the muscle fibre force generating capacity but did not affect muscle wasting. Nevertheless, this work strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients.

Furthermore, we observed significant differences in the phenotype and mechanism underlying the loss of force generating capacity between the diaphragm and limb muscles in response to controlled mechanical ventilation (CMV) and immobilisation. This knowledge will have to be taken into account when designing intervention strategies to alleviate the muscle wasting and weakness that occurs in mechanically ventilated and immobilized ICU patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 862
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-192531 (URN)978-91-554-8586-3 (ISBN)
Public defence
2013-03-08, Hedstrandsalen, Ingång 70, bv, Akademiska sjukhuset, Uppsala, 13:15 (English)
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Available from: 2013-02-14 Created: 2013-01-22 Last updated: 2016-07-19

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Corpeno, RebecaDworkin, BarryCacciani, NicolaSalah, HebaBergman, Hilde-MarleneGustafson, Ann-MarieHedström, YvetteArtemenko, KonstantinBergquist, JonasLarsson, Lars

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Corpeno, RebecaDworkin, BarryCacciani, NicolaSalah, HebaBergman, Hilde-MarleneGustafson, Ann-MarieHedström, YvetteArtemenko, KonstantinBergquist, JonasLarsson, Lars
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