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Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease
- Source :
- Ottenheijm, C A C, Heunks, L M A, Li, Y P, Jin, B, Minnaard, R, Van Hees, H W H & Dekhuijzen, P N R 2006, ' Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease ', American Journal of Respiratory and Critical Care Medicine, vol. 174, no. 9, pp. 997-1002 . https://doi.org/10.1164/rccm.200605-721OC, American Journal of Respiratory and Critical Care Medicine, 174, 9, pp. 997-1002, American Journal of Respiratory and Critical Care Medicine, 174(9), 997-1002. American Thoracic Society, American Journal of Respiratory and Critical Care Medicine, 174, 997-1002
- Publication Year :
- 2006
-
Abstract
- Contains fulltext : 49998.pdf (Publisher’s version ) (Closed access) RATIONALE: Studies show that the myosin content of the diaphragm in patients with mild to moderate chronic obstructive pulmonary disease (COPD) is reduced, compromising diaphragm contractile performance. The mechanisms for reduced contractile protein content are unknown. In the present study we hypothesized that the loss of contractile protein content is associated with activation of the ubiquitin-proteasome pathway in the diaphragm of patients with mild to moderate COPD. METHODS: Proteolytic activity of isolated 20S proteasomes was determined in diaphragm biopsies from patients with and without COPD (predicted mean FEV1, 66 and 93%, respectively). In addition, we determined 20S proteasome subunit C8 protein levels by means of Western blotting, ubiquitin-ligase mRNA levels by means of real-time polymerase chain reaction, and caspase-3 activity by determining the hydrolysis of fluorogenic substrates. RESULTS: The 20S proteasome activity was about threefold increased in the diaphragm of patients with COPD. C8 protein levels were not significantly different between COPD and non-COPD diaphragm, indicating increased specific activity of individual proteasomes, rather than an increased number of proteasomes. mRNA levels of the muscle-specific ubiquitin-ligase MAFbx were significantly higher in diaphragm from patients with COPD compared with patients without COPD. Caspase-3-mediated cleavage of actomyosin complexes is considered an initial step in muscle wasting, yielding fragments that can be degraded by the ubiquitin-proteasome pathway. In line with the increased ubiquitin-proteasome activity, caspase-3 activity was higher in diaphragm homogenates from patients with COPD. CONCLUSIONS: The present study is the first to demonstrate increased activity of the ubiquitin-proteasome pathway in COPD diaphragm. Importantly, these changes occur in patients with only mild to moderate COPD (Global Initiative for Chronic Obstructive Lung Disease stage I/II).
- Subjects :
- Male
Pulmonary and Respiratory Medicine
Proteasome Endopeptidase Complex
medicine.medical_specialty
Ubiquitin-Protein Ligases
Diaphragm
Muscle Proteins
C. Chronic Obstructive Pulmonary Disease
Caspase 3
Myosins
Critical Care and Intensive Care Medicine
Tripartite Motif Proteins
Pulmonary Disease, Chronic Obstructive
Ubiquitin
Internal medicine
Intensive care
Myosin
medicine
Humans
Heart, lung and circulation [UMCN 2.1]
Aged
COPD
SKP Cullin F-Box Protein Ligases
biology
business.industry
Respiratory disease
Middle Aged
musculoskeletal system
medicine.disease
Immunohistochemistry
Obstructive lung disease
respiratory tract diseases
Pathogenesis and modulation of inflammation [N4i 1]
Endocrinology
Proteasome
Immunology
biology.protein
Female
Microbial pathogenesis and host defense [UMCN 4.1]
business
Muscle Contraction
Subjects
Details
- ISSN :
- 1073449X
- Volume :
- 174
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory and Critical Care Medicine
- Accession number :
- edsair.doi.dedup.....cb948ddc635e4ee4a4114ea6ee7a02b6