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Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness

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Abstract

Importance

Intensive care unit (ICU)-acquired muscle wasting is a devastating complication leading to persistent weakness and functional disability. The mechanisms of this myopathy are unclear, but a disturbed balance of myosin heavy chain (MyHC) is implicated.

Objective

To investigate pathways of myosin turnover in severe critically ill patients at high risk of ICU-acquired weakness.

Design

Prospective, mechanistic, observational study.

Setting

Interdisciplinary ICUs of a university hospital.

Participants

Twenty-nine patients with Sequential Organ Failure Assessment (SOFA) scores of at least 8 on three consecutive days within the first 5 days in ICU underwent two consecutive open skeletal muscle biopsies from the vastus lateralis at median days 5 and 15. Control biopsy specimens were from healthy subjects undergoing hip-replacement surgery.

Interventions

None.

Main outcome(s) and measure(s)

Time-dependent changes in myofiber architecture, MyHC synthesis, and degradation were determined and correlated with clinical data.

Results

ICU-acquired muscle wasting was characterized by early, disrupted myofiber ultrastructure followed by atrophy of slow- and fast-twitch myofibers at later time points. A rapid decrease in MyHC mRNA and protein expression occurred by day 5 and persisted at day 15 (P < 0.05). Expression of the atrophy genes MuRF-1 and Atrogin1 was increased at day 5 (P < 0.05). Early MuRF-1 protein content was closely associated with late myofiber atrophy and the severity of weakness.

Conclusions and relevance

Decreased synthesis and increased degradation of MyHCs contribute to ICU-acquired muscle wasting. The rates and time frames suggest that pathogenesis of muscle failure is initiated very early during critical illness. The persisting reduction of MyHC suggests that sustained treatment is required.

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Acknowledgments

We are thankful for the patience and courage of our patients and their consenting relatives. We thank Anika Lindner and Josefine Russ for technical assistance. We thank Friedrich C. Luft, MD, FACP for his continued support and editorial assistance. The Deutsche Forschungsgemeinschaft (FI 965/2-1, FI 965/4-1 and La668/14-1, KFO 192—WE 4386/1-2), Muscular Dystrophy Association, Marie Curie International Reintegration grant (FP7-PEOPLE-2007-4-3-IRG), and the Deutsche Gesellschaft für Muskelkranke supported this work.

Conflicts of interest

The authors are not aware of any conflicts of interest.

Author information

Authors and Affiliations

  1. Anesthesiology and Operative Intensive Care Medicine, Charité–Universitätsmedizin Berlin, Campus Virchow and Campus Mitte, Berlin, Germany

    Tobias Wollersheim, Martin Krebs, Anja Luther-Schroeder, Kurt Haas, Theresa Radtke, Claudia Spies & Steffen Weber-Carstens

  2. Experimental and Clinical Research Center (ECRC), A Cooperation Between Max-Delbrück-Centrum and Charité–Universitätsmedizin Berlin, Campus Buch, Lindenberger Weg 80, 13125, Berlin, Germany

    Janine Woehlecke, Jida Hamati, Doerte Lodka, Claudia Langhans, Simone Spuler, Joachim Spranger & Jens Fielitz

  3. Center for Musculoskeletal Surgery, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Christian Kleber

  4. Universitätsmedizin Mannheim, Mannheim, Germany

    Siegfried Labeit

  5. NeuroCure Clinical Research Center, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Markus Schuelke

  6. Department of Endocrinology, Diabetes and Nutrition, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Joachim Spranger

  7. Center for Cardiovascular Research, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Joachim Spranger

  8. Department of Cardiology, Charité–Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany

    Jens Fielitz

Authors
  1. Tobias Wollersheim
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  2. Janine Woehlecke
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  3. Martin Krebs
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  4. Jida Hamati
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  5. Doerte Lodka
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  6. Anja Luther-Schroeder
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  7. Claudia Langhans
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  8. Kurt Haas
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  9. Theresa Radtke
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  10. Christian Kleber
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  11. Claudia Spies
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  12. Siegfried Labeit
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  13. Markus Schuelke
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  14. Simone Spuler
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  15. Joachim Spranger
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  16. Steffen Weber-Carstens
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  17. Jens Fielitz
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Corresponding author

Correspondence to Jens Fielitz.

Additional information

T. Wollersheim and J. Woehlecke contributed equally to this work.

S. Weber-Carstens and J. Fielitz contributed equally to this work.

Take-home message: Intensive care unit (ICU)-acquired muscle wasting is a devastating complication leading to persistent weakness and functional disability. We demonstrate that decreased synthesis and increased degradation of myosin heavy chains contribute to ICU-acquired muscle wasting, and conclude that therapeutic interventions must be initiated very early during critical illness.

Trial registration

The study was registered at http://www.controlled-trials.com as ISRCTN77569430.

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Wollersheim, T., Woehlecke, J., Krebs, M. et al. Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness. Intensive Care Med 40, 528–538 (2014). https://doi.org/10.1007/s00134-014-3224-9

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  • DOI: https://doi.org/10.1007/s00134-014-3224-9

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