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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Biopsy
  • Blotting, Western
  • Case-Control Studies
  • Critical Illness*
  • Diaphragm / pathology
  • Diaphragm / physiopathology*
  • Disease Models, Animal
  • Female
  • Humans
  • Length of Stay
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle Proteins
  • Muscle Weakness / etiology
  • Muscle Weakness / pathology
  • Muscle Weakness / physiopathology*
  • Muscular Atrophy / etiology
  • Muscular Atrophy / pathology
  • Muscular Atrophy / physiopathology*
  • Netherlands
  • Proteasome Endopeptidase Complex / metabolism*
  • Respiration, Artificial / adverse effects*
  • Tripartite Motif Proteins
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases
  • Young Adult


  • Muscle Proteins
  • Tripartite Motif Proteins
  • Ubiquitin
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex