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Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms
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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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.

Place, publisher, year, edition, pages
2011. Vol. 589, no 8, 2007-2026 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-152844DOI: 10.1113/jphysiol.2010.202044ISI: 000289527200018OAI: oai:DiVA.org:uu-152844DiVA: diva2:414476
Available from: 2011-05-03 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Mechanisms Underlying Intensive Care Unit Muscle Wasting: Intervention Strategies in an Experimental Animal Model and in Intensive Care Unit Patients
Open this publication in new window or tab >>Mechanisms Underlying Intensive Care Unit Muscle Wasting: Intervention Strategies in an Experimental Animal Model and in Intensive Care Unit Patients
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
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:nbn:se:uu:diva-173466 (URN)978-91-554-8387-6 (ISBN)
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
2. 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)
Opponent
Supervisors
Available from: 2013-02-14 Created: 2013-01-22 Last updated: 2016-07-19

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Ochala, JulienGustafson, Ann-MarieDiez, Monica LlanoRenaud, GuillaumeLi, MeishanAare, SudhakarBanduseela, Varuna C.Hedström, YvetteDworkin, BarryLarsson, Lars

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