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Am J Respir Crit Care Med. 2015 May 15;191(10):1126-38. doi: 10.1164/rccm.201412-2214OC.

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

Author information

1
1 Department of Physiology.

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.

KEYWORDS:

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

Comment in

PMID:
25760684
PMCID:
PMC4451621
DOI:
10.1164/rccm.201412-2214OC
[Indexed for MEDLINE]
Free PMC Article

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