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

Pleuni E. Hooijman, Albertus Beishuizen, Christian C. Witt, Monique C. de Waard, Armand R.J. Girbes, Angelique M.E. Spoelstra-de Man, Hans W.M. Niessen, Emmy Manders, Hieronymus W.H. van Hees, Charissa E. van den Brom, Vera Silderhuis, Michael W. Lawlor, Siegfried Labeit, Ger J.M. Stienen, Koen J. Hartemink, Marinus A. Paul, Leo M.A. Heunks, Coen A.C. Ottenheijm

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

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 (US)
Pages (from-to)1126-1138
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume191
Issue number10
DOIs
StatePublished - May 15 2015
Externally publishedYes

Keywords

  • diaphragm weakness
  • mechanical ventilation
  • single muscle fiber
  • weaning failure

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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