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Mechanisms Underlying Intensive Care Unit Muscle Wasting: Intervention Strategies in an Experimental Animal Model and in Intensive Care Unit Patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Critically ill patients admitted to the intensive care unit (ICU) commonly develop severe muscle wasting and weakness and consequently impaired muscle function. This not only delays respirator weaning and ICU discharge, but has deleterious effects on morbidity, mortality, financial costs, and quality of life of survivors. Acute Quadriplegic Myopathy (AQM) is one of the most common neuromuscular disorders underlying ICU muscle wasting and paralysis, and is a consequence of modern intensive care interventions, although the exact causes remain unclear. Muscle gene/protein expression, intracellular signalling, post-translational modifications, muscle membrane excitability, and contractile properties at the single muscle fibre level were explored in order to unravel the mechanisms underlying the muscle wasting and weakness associated with AQM and how this can be counteracted by specific intervention strategies. A unique experimental rat ICU model was used to address the mechanistic and therapeutic aspects of this condition, allowing time-resolved studies for a period of two weeks. Subsequently, the findings obtained from this model were translated into a clinical study. The obtained results showed that the mechanical silencing of skeletal muscle, i.e., absence of external strain (weight bearing) and internal strain (myosin-actin activation) due to the pharmacological paralysis or sedation associated with the ICU intervention, is likely to be the primary mechanism triggering the preferential myosin loss and muscle wasting, features specifically characteristic of AQM. Moreover, mechanical silencing induces a specific gene expression pattern as well as post-translational modifications in the motor domain of myosin that may be critical for both function and for triggering proteolysis. The higher nNOS expression found in the ICU patients and its cytoplasmic dislocation are indicated as a probable mechanism underlying these highly specific modifications. This work also demonstrated that passive mechanical loading is able to attenuate the oxidative stress associated with the mechanical silencing and induces positive effects on muscle function, i.e., alleviates the loss of force-generating capacity that underlie the ICU intervention, supporting the importance of early physical therapy in immobilized, sedated, and mechanically ventilated ICU patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 781
Keyword [en]
acute quadriplegic myopathy, intensive care unit, myosin, regulation of contraction, muscle atrophy, mechanical loading, mobilization
National Category
Clinical Medicine
Research subject
Clinical Neurophysiology
Identifiers
URN: urn:nbn:se:uu:diva-173466ISBN: 978-91-554-8387-6 (print)OAI: oai:DiVA.org:uu-173466DiVA: diva2:523643
Public defence
2012-06-14, Hedstrandsalen, Akademiska sjukhuset, Ingång 70, bv, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-05-24 Created: 2012-04-25 Last updated: 2016-07-19Bibliographically approved
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. Muscle wasting and the temporal gene expression pattern in a novel rat intensive care unit model
Open this publication in new window or tab >>Muscle wasting and the temporal gene expression pattern in a novel rat intensive care unit model
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2011 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 12, 602- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. To elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness associated with AQM, a gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals.

RESULTS:

During the observation period, 1583 genes were significantly up- or down-regulated by factors of two or greater. A significant temporal gene expression pattern was constructed at short (6h-4 days), intermediate (5-8 days) and long (9-14 days) durations. A striking early and maintained up-regulation (6h-14d) of muscle atrogenes (muscle ring-finger 1/tripartite motif-containing 63 and F-box protein 32/atrogin-1) was observed, followed by an upregulation of the proteolytic systems at intermediate and long durations (5-14d). Oxidative stress response genes and genes that take part in amino acid catabolism, cell cycle arrest, apoptosis, muscle development, and protein synthesis together with myogenic factors were significantly up-regulated from 5 to 14 days. At 9-14 d, genes involved in immune response and the caspase cascade were up-regulated. At 5-14d, genes related to contractile (myosin heavy chain and myosin binding protein C), regulatory (troponin, tropomyosin), developmental, caveolin-3, extracellular matrix, glycolysis/gluconeogenesis, cytoskeleton/sarcomere regulation and mitochondrial proteins were down-regulated. An activation of genes related to muscle growth and new muscle fiber formation (increase of 3 myogenic factors and JunB and down-regulation of myostatin) and up-regulation of genes that code protein synthesis and translation factors were found from 5 to 14 days.

CONCLUSIONS:

Novel temporal patterns of gene expression have been uncovered, suggesting a unique, coordinated and highly complex mechanism underlying the muscle wasting associated with AQM in ICU patients and providing new target genes and avenues for intervention studies.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-164314 (URN)10.1186/1471-2164-12-602 (DOI)000299899100001 ()22165895 (PubMedID)
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically approved
3. 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
4. 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

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