Faculty Collaboration Database

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

Date

03/12/2015

Pubmed ID

25760684

Pubmed Central ID

PMC4451621

DOI

10.1164/rccm.201412-2214OC

Scopus ID

2-s2.0-84989782434 (requires institutional sign-in at Scopus site)   143 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.

Author List

Hooijman PE, Beishuizen A, Witt CC, de Waard MC, Girbes AR, Spoelstra-de Man AM, Niessen HW, Manders E, van Hees HW, van den Brom CE, Silderhuis V, Lawlor MW, Labeit S, Stienen GJ, Hartemink KJ, Paul MA, Heunks LM, Ottenheijm CA

Author

Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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