Introduction Sarcopenia contributes significantly to decreased exercise tolerance, reduced quality of life, and worse overall prognosis, independent of lung function severity in chronic respiratory disease including bronchiectasis. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) contribute to muscle wasting. We hypothesized that ER stress is increased in muscles of bronchiectasis patients with sarcopenia. Methods In the vastus lateralis (VL) of patients with bronchiectasis and sarcopenia (n=20) and healthy controls (n=10), markers indicative of ER stress, key components of the UPR signaling network, including ATF6, PERK, and IRE1, and molecular indicators of proteolytic activity and autophagy were measured. Patients and controls were clinically evaluated. Patients were clinically stable, non-smokers, and had mild to moderate disease severity (BSI score), and exhibited significantly reduced body weight, BMI, FFMI, QMVC, handgrip strength, and exercise capacity compared to the age- and sex-matched controls. Results In VL of patients compared to the controls, ER stress markers ATF4 and XBP1 protein levels and those of atrogin-1, MuRF-1, 20S proteasome C8 subunit, and p62 increased, while inverse correlations were detected between muscle protein atrogin-1 levels and BMI, FFMI, and ND-QMVC. Conclusions Bronchiectasis patients with sarcopenia exhibit marked skeletal muscle impairment, systemic inflammation, and selective activation of the ATF4 and XBP1 arms of the UPR. These molecular alterations were accompanied by increased proteolysis and signs of impaired autophagy. Targeting these pathways may offer novel therapeutic strategies to preserve muscle mass and function in bronchiectasis, ultimately improving quality of life and clinical outcomes.
Núñez-Robainas et al. (Fri,) studied this question.