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Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease.

ABSTRACT: 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.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.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.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).

SUBMITTER: Ottenheijm CA

PROVIDER: S-EPMC2648103 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease.

Ottenheijm Coen A C CA Heunks Leo M A LM Li Yi-Ping YP Jin Bingwen B Minnaard Ronnie R van Hees Hieronymus W H HW Dekhuijzen P N Richard PN

American journal of respiratory and critical care medicine 20060817 9

<h4>Rationale</h4>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.<h4>Methods</h4>P ...[more]

PMID: 16917114

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Project description:The objectives of the study were to identify the factors that limit diaphragmatic mobility and evaluate the therapeutic results of the monitoring methods previously used in patients with chronic obstructive pulmonary disease. The PubMed, Web of Science, Scopus, and LILACS databases were used. A gray literature search was conducted with Google scholar. PRISMA was used, and the bias risk analysis adapted from the Cochrane Handbook for clinical trials and, for other studies, the Downs and Black checklist were used. Twenty-five articles were included in the qualitative synthesis analysis on physiotherapeutic techniques and diaphragmatic mobility. Eight clinical trials indicated satisfactory domains, and on the Downs and Black scale, 17 cohort studies were evaluated to have an acceptable score. Different conditions must be observed; for example, for postoperative assessments the supine position is suggested to be the most appropriate position to verify diaphragm excursion, although it has been shown to be associated with difficulty of restriction and matching in samples. Therefore, we identified the need for contemporary adjustments and strategies that used imaging instruments, preferably in the dorsal position. Therapeutic evidence on the association between the instrumental method and diaphragmatic mobility can be controversial. The ultrasound measurements indicated some relevance for different analyses, for pulmonary hyperinflation as well as diaphragm thickness and mobilization, in COPD patients. In particular, the study suggests that the ultrasound technique with B-mode for analysis and M-mode for diaphragmatic excursion be used with a 2 - 5 MHz with the patient in the supine position. However, the methods used to monitor diaphragm excursion should be adapted to the conditions of the patients, and additional investigations of their characteristics should be performed. More selective inclusion criteria and better matching in the samples are very important. In addition, more narrow age, sex and weight categories are important, especially in patients with chronic obstructive pulmonary disease.

Dataset Information

Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease.

Publications

Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease.

Similar Datasets

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