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Intensive care Muscle Wasting and Weakness: Underlying Mechanisms, Muscle Specific Differences and a Specific Intervention Strategy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
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: urn:nbn:se:uu:diva-192531ISBN: 978-91-554-8586-3 (print)OAI: oai:DiVA.org:uu-192531DiVA: diva2:599857
Public defence
2013-03-08, Hedstrandsalen, Ingång 70, bv, Akademiska sjukhuset, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-02-14 Created: 2013-01-22 Last updated: 2016-07-19
List of papers
1. Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms
Open this publication in new window or tab >>Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms
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2011 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 589, no 8, 2007-2026 p.Article in journal (Refereed) Published
Abstract [en]

Non-technical summary Wasting and severely impaired function of skeletal muscle is frequently observed in critically ill intensive care unit (ICU) patients, with negative consequences for recovery and quality of life. An experimental rat ICU model has been used to study the mechanisms underlying this unique wasting condition in neuromuscularly blocked and mechanically ventilated animals at durations varying between 6 h and 2 weeks. The complete 'mechanical silencing' of skeletal muscle (removal of both weight bearing and activation) resulted in a specific myopathy frequently observed in ICU patients and characterized by a preferential loss of the motor protein myosin. A highly complex and coordinated protein synthesis and degradation system was observed in the time-resolved analyses. It is suggested the 'mechanical silencing' of skeletal muscle is a dominating factor triggering the specific myopathy associated with the ICU intervention, and strongly supporting the importance of interventions counteracting the complete unloading in ICU patients.The muscle wasting and impaired muscle function in critically ill intensive care unit (ICU) patients delay recovery from the primary disease, and have debilitating consequences that can persist for years after hospital discharge. It is likely that, in addition to pernicious effects of the primary disease, the basic life support procedures of long-term ICU treatment contribute directly to the progressive impairment of muscle function. This study aims at improving our understanding of the mechanisms underlying muscle wasting in ICU patients by using a unique experimental rat ICU model where animals are mechanically ventilated, sedated and pharmacologically paralysed for duration varying between 6 h and 14 days. Results show that the ICU intervention induces a phenotype resembling the severe muscle wasting and paralysis associated with the acute quadriplegic myopathy (AQM) observed in ICU patients, i.e. a preferential loss of myosin, transcriptional down-regulation of myosin synthesis, muscle atrophy and a dramatic decrease in muscle fibre force generation capacity. Detailed analyses of protein degradation pathways show that the ubiquitin proteasome pathway is highly involved in this process. A sequential change in localisation of muscle-specific RING finger proteins 1/2 (MuRF1/2) observed during the experimental period is suggested to play an instrumental role in both transcriptional regulation and protein degradation. We propose that, for those critically ill patients who develop AQM, complete mechanical silencing, due to pharmacological paralysis or sedation, is a critical factor underlying the preferential loss of the molecular motor protein myosin that leads to impaired muscle function or persisting paralysis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-152844 (URN)10.1113/jphysiol.2010.202044 (DOI)000289527200018 ()
Available from: 2011-05-03 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
2. Sparing of muscle mass and function by passive loading in an experimental intensive care unit model
Open this publication in new window or tab >>Sparing of muscle mass and function by passive loading in an experimental intensive care unit model
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2013 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 591, no 5, 1385-1402 p.Article in journal (Refereed) Published
Abstract [en]

The response to mechanical stimuli, i.e., tensegrity, plays an important role in regulating cell physiological and pathophysiological function and the mechanical silencing observed in intensive care unit (ICU) patients leads to a severe and specific muscle wasting condition. This study aims at unravelling the underlying mechanisms and the effects of passive mechanical loading on skeletal muscle mass and function at the gene, protein and cellular levels. A unique experimental rat ICU model has been used allowing long-term (weeks) time-resolved analyses of the effects of standardized unilateral passive mechanical loading on skeletal muscle size and function and underlying mechanisms. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. the unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle mass and function is likely a consequence of a reduced oxidative stress revealed by lower levels of carbonylated proteins, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle size and function associated with the mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients.

National Category
Clinical Laboratory Medicine
Research subject
Clinical Neurophysiology
Identifiers
urn:nbn:se:uu:diva-189247 (URN)10.1113/jphysiol.2012.248724 (DOI)000315514300018 ()23266938 (PubMedID)
Available from: 2012-12-28 Created: 2012-12-28 Last updated: 2017-12-06Bibliographically approved
3. Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading
Open this publication in new window or tab >>Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading
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2012 (English)In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 16, no 5, R209- p.Article in journal (Refereed) Published
Abstract [en]

ABSTRACT: INTRODUCTION: Critical ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life of survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model have shown that the "mechanical silencing" associated with the ICU condition is the primary triggering factor. This study aims at (1) unraveling the mechanisms underlying CIM, and (2) evaluating the effects of a specific intervention aiming at reducing the mechanical silencing in sedated and mechanically ventilated ICU patients. METHODS: Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading 10 hours per day (2.5 hours, 4 times) for 9 +/- 1 days. RESULTS: These patients developed a phenotype considered pathognomonic of CIM, i.e., severe muscle wasting and a preferential myosin loss (P<0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of nNOS. Passive mechanical loading for 9 +/- 1 resulted in a 35% higher specific force (P<0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. CONCLUSIONS: Mechanical silencing is suggested to be a primary mechanism underlying CIM, i.e., triggering the myosin loss, muscle wasting and myosin PTMs. The higher nNOS expression found in the ICU patients and its cytoplasmic translocation are forwarded as a probable mechanism underlying these modifications. The positive effect of passive loading on muscle fiber function strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients.

National Category
Clinical Laboratory Medicine
Research subject
Clinical Neurophysiology
Identifiers
urn:nbn:se:uu:diva-183734 (URN)10.1186/cc11841 (DOI)000317499900046 ()23098317 (PubMedID)
Note

De två (2) första författarna delar förstaförfattarskapet.

Available from: 2012-11-01 Created: 2012-11-01 Last updated: 2017-12-07Bibliographically approved
4. Time-course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat
Open this publication in new window or tab >>Time-course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat
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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.

National Category
Physiology Neurology
Identifiers
urn:nbn:se:uu:diva-192529 (URN)10.1113/jphysiol.2014.277962 (DOI)000341771400013 ()
Funder
Swedish Research Council, 8651, 4423
Available from: 2013-01-22 Created: 2013-01-22 Last updated: 2017-12-06Bibliographically approved

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