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

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.

• Authors: 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
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 191 Issue 10 Pg. 1126-38 (May 15 2015) ISSN: 1535-4970 [Electronic] United States
• PMID: 25760684 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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