Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness
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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.
To investigate pathways of myosin turnover in severe critically ill patients at high risk of ICU-acquired weakness.
Prospective, mechanistic, observational study.
Interdisciplinary ICUs of a university hospital.
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.
Main outcome(s) and measure(s)
Time-dependent changes in myofiber architecture, MyHC synthesis, and degradation were determined and correlated with clinical data.
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.
KeywordsICUAW MuRF-1 Myosin degradation Inflammation Muscle atrophy dmCMAP
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.
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