Diaphragm muscle fiber weakness and ubiquitin-proteasome activation in critically ill patients

P.E. Hooijman, A. Beishuizen, C.C. Witt, M.C. de Waard, A.R.J. Girbes, A.M.E. Spoelstra-de Man, H.W. Niessen, E. Manders, H.W.H. van Hees, C.E. van den Brom, V. Silderhuis, M.W. Lawlor, S. Labeit, G.J.M. Stienen, K.J. Hartemink, M.A. Paul, L.M.A. Heunks, C.A.C. Ottenheijm

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

RATIONALE: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.

OBJECTIVES: We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm.

METHODS: We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation.

MEASUREMENTS AND MAIN RESULTS: Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.

CONCLUSIONS: These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.

Original languageEnglish
Pages (from-to)1126-1138
Number of pages13
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume191
Issue number10
DOIs
Publication statusPublished - 15 May 2015

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