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Muscle atrophy and preferential loss of myosin in prolonged critically ill patients*

Derde, Sarah PhD; Hermans, Greet MD, PhD; Derese, Inge BSc; Güiza, Fabian PhD; Hedström, Yvette BSc; Wouters, Pieter J. MSc; Bruyninckx, Frans MD, PhD; D'Hoore, André MD, PhD; Larsson, Lars MD, PhD; Van den Berghe, Greet MD, PhD; Vanhorebeek, Ilse PhD

doi: 10.1097/CCM.0b013e31822d7c18
Clinical Investigations

Objective: Muscle weakness contributes to prolonged rehabilitation and adverse outcome of critically ill patients. Distinction between a neurogenic and/or myogenic underlying problem is difficult using routine diagnostic tools. Preferential loss of myosin has been suggested to point to a myogenic component. We evaluated markers of muscle atrophy and denervation, and the myosin/actin ratio in limb and abdominal wall skeletal muscle of prolonged critically ill patients and matched controls in relation to insulin therapy and known risk factors for intensive care unit-acquired weakness.

Design: Secondary analysis of two large, prospective, single-center randomized clinical studies.

Setting: University hospital surgical and medical intensive care unit.

Patients: Critically ill patients and matched controls.

Interventions: Intensive care unit patients had been randomized to blood glucose control to 80–110 mg/dL with insulin infusion or conventional glucose management, where insulin was only administered when glucose levels rose above 215 mg/dL.

Measurements and Main Results: As compared with controls, rectus abdominis and vastus lateralis muscle of critically ill patients showed smaller myofiber size, decreased mRNA levels for myofibrillar proteins, increased proteolytic enzyme activities, and a lower myosin/actin ratio, virtually irrespective of insulin therapy. Increased forkhead box O1 action may have played a role. Most alterations were more severe in patients treated with corticosteroids. Duration of corticosteroid treatment, independent of duration of intensive care unit stay or other risk factors, was a dominant risk factor for a low myosin/actin ratio. The immature acetylcholine receptor subunit γ messenger RNA expression was elevated in vastus lateralis, independent of the myosin/actin ratio.

Conclusions: Both limb and abdominal wall skeletal muscles of prolonged critically ill patients showed downregulation of protein synthesis at the gene expression level as well as increased proteolysis. This affected myosin to a greater extent than actin, resulting in a decreased myosin/actin ratio. Muscle atrophy was not ameliorated by intensive insulin therapy, but possibly aggravated by corticosteroids.

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From the Departments of Intensive Care Medicine (SD, ID, FG, PJW, GVdB, IV), General Internal Medicine (GH), Physical Medicine and Rehabilitation (FB), and Abdominal Surgery (ADH), Katholieke Universiteit Leuven, Leuven, Belgium; and Department of Clinical Neurophysiology (YH, LL), Uppsala University, Sweden.

* See also p. 314.

Drs. Derde and Hermans contributed equally to this manuscript.

Supported, in part, by the Fund for Scientific Research (FWO), Flanders, Belgium (G.0585.09), the Research Council of the Katholieke Universiteit Leuven (GOA2007/14), l'Association Française contre les Myopathies, the European Commission MyoAge (EC Fp7 CT-223756), and the Swedish Research Council (8651). GH was a Clinical Research Fellow of the Fund for Scientific Research (FWO), Flanders, Belgium and currently a postdoctoral Fellow for the Clinical Research Fund (KOF) of the University Hospitals Leuven. GVdB by the University of Leuven, receives long-term structural research financing via the Methusalem program, funded by the Flemish Government.

The authors have not disclosed any potential conflicts of interest.

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© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins