Affiliation:
1. Pulmonology Department-Muscle and Respiratory System Research Unit, Institut Hospital del Mar d’Investigacions Mèdiques-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Barcelona, Spain
2. Centro de Investigación en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
3. Thoracic Surgery Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
Abstract
Respiratory muscle dysfunction is common in patients with chronic obstructive pulmonary disease (COPD). Chronic contractile activity induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in animals (animals and humans). We hypothesized that the respiratory muscle dysfunction associated with COPD may upregulate ER stress and UPR expression in diaphragm of stable patients with different degrees of airway obstruction and normal body composition. In diaphragm muscle specimens of patients with mild and moderate-to-severe COPD with preserved body composition and non-COPD controls (thoracotomy because of lung localized neoplasms), expression of protein misfolding (ER stress) and UPR markers, proteolysis and apoptosis (qRT-PCR and immunoblotting), and protein aggregates (lipofuscin, histology) were quantified. All patients and non-COPD controls were also clinically evaluated: lung and muscle functions and exercise capacity. Compared with non-COPD controls, patients exhibited mild and moderate-to-severe airflow limitation and diffusion capacity and impaired exercise tolerance and diaphragm strength. Moreover, compared with the controls, in the diaphragm of the COPD patients, slow-twitch fiber proportions increased, gene expression but not protein levels of protein disulfide isomerase family A member 3 and phosphatidylinositol 3-kinase catalytic subunit type 3 were upregulated, and no significant differences were found in markers of UPR transmembrane receptor pathways (activating transcription factor-6, inositol-requiring enzyme-1α, and protein kinase-like ER kinase), lipofuscin aggregates, proteolysis, or apoptosis. In stable COPD patients with a wide range of disease severity, reduced diaphragm force of contraction, and normal body composition, ER stress and UPR signaling were not induced in the main respiratory muscle. These findings imply that ER stress and UPR are probably not involved in the documented diaphragm muscle dysfunction (reduced strength) observed in all the study patients, even in those with severe airflow limitation. Hence, in stable COPD patients with normal body composition, therapeutic strategies targeted to treat diaphragm muscle dysfunction should not include UPR modulators, even in those with a more advanced disease. NEW & NOTEWORTHY In stable chronic obstructive pulmonary disease patients with a wide range of disease severity, diaphragm muscle weakness, and normal body composition, endoplasmic reticulum stress and unfolded protein response (UPR) signaling were not induced in the main respiratory muscle. These findings imply that endoplasmic reticulum stress and UPR are not involved in the documented diaphragm muscle dysfunction observed in the study patients, even in those with severe airflow limitation. In stable chronic obstructive pulmonary disease patients with normal body composition, therapeutic strategies should not include UPR modulators.
Funder
Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Carlos III Health Institute)
Sociedad Española de Neumologia y Cirugia Toracica
Fundació Catalana de Pneumologia
European Respiratory Society COPD Research Award
Publisher
American Physiological Society
Subject
Physiology (medical),Physiology
Cited by
17 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献