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- Title
Diaphragm muscle fiber weakness and ubiquitin-proteasome activation in critically ill patients.
- Authors
Hooijman, Pleuni E; Beishuizen, Albertus; Witt, Christian C; de Waard, Monique C; Girbes, Armand R J; Spoelstra-de Man, Angelique M E; Niessen, Hans W M; Manders, Emmy; van Hees, Hieronymus W H; van den Brom, Charissa E; Silderhuis, Vera; Lawlor, Michael W; Labeit, Siegfried; Stienen, Ger J M; Hartemink, Koen J; Paul, Marinus A; Heunks, Leo M A; Ottenheijm, Coen A C
- Abstract
<bold>Rationale: </bold>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. <bold>Objectives: </bold>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. <bold>Methods: </bold>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. <bold>Measurements and Main Results: </bold>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. <bold>Conclusions: </bold>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.
- Publication
American Journal of Respiratory & Critical Care Medicine, 2015, Vol 191, Issue 10, p1126
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201412-2214OC