Objective Skeletal muscle dysfunction is an important comorbidity in patients with chronic obstructive pulmonary disease (COPD), and is associated with poor quality of life and reduced survival, but the mechanisms involved remain elusive. Ferroptosis is a newly discovered type of cell death resulting from iron‐dependent lipid peroxide accumulation. The purpose of this study was to examine whether ferroptosis is involved in COPD-associated skeletal muscle dysfunction. Methods A mouse model of COPD was established after 24 weeks of cigarette smoke (CS) exposure, and mRNA sequencing, hematoxylin-eosin (H&E) staining, immunostaining (IF), RT-PCR, and Western blot were utilized to identify the changes in gastrocnemius muscles. In vitro, C2C12 myotubes were treated with CS extract (CSE) and evaluated for ferroptosis-related molecules. The pathways regulating ferroptosis were then explored in CSE-stimulated myotubes. Results Compared with controls, COPD mice showed an enriched ferroptosis pathway. Gpx4 was decreased, while hypoxia-inducible factor (Hif) 2α was increased, at gene and protein levels. A reduced level of GSH, but increased cell death, Fe 2+ , lipid ROS, LPO, and 4-HNE were observed in COPD mice or in CSE-stimulated C2C12 myotubes, which could be ameliorated by ferroptosis inhibitors. The expression of myostatin (MSTN) was enhanced in COPD mice and CSE-stimulated myotubes. MSTN up-regulated HIF2α expression and led to ferroptosis in myotubes, whereas inhibition of MSTN binding to its receptor or inhibition/knockdown of HIF2α resulted in decreased cell death, and partially restored GPX4 and GSH. Conclusion CS exposure induced ferroptosis in vivo and in vitro. Mechanistically, CS-exposure upregulated MSTN which further induced ferroptosis through HIF2α in skeletal muscles, which may contribute to muscle dysfunction through impairing metabolic capacity and decreasing muscle fiber numbers, revealing a potential novel therapeutic target for COPD-related skeletal muscle dysfunction.

Background COPD patients living in Tibet are exposed to specific environments and different risk factors and probably have different characteristics of COPD from those living in flatlands. We aimed to describe the distinction between stable COPD patients permanently residing at the Tibet plateau and those in flatlands. Methods We conducted an observational cross-sectional study that enrolled stable COPD patients from Tibet Autonomous Region People’s Hospital (Plateau Group) and Peking University Third Hospital (Flatland Group), respectively. Their demographic information, clinical features, spirometry test, blood routine and high-resolution chest CT were collected and evaluated. Results A total of 182 stable COPD patients (82 from plateau and 100 from flatland) were consecutively enrolled. Compared to those in flatlands, patients in plateau had a higher proportion of females, more biomass fuel use and less tobacco exposure. CAT score and frequency of exacerbation in the past year were higher in plateau patients. The blood eosinophil count was lower in plateau patients, with fewer patients having an eosinophil count ≥300/μL. On CT examination, the proportions of previous pulmonary tuberculosis and bronchiectasis were higher in plateau patients, but emphysema was less common and milder. The ratio of diameters of pulmonary artery to aorta ≥1 was more often in plateau patients. Conclusion Patients with COPD living at Tibet Plateau had a heavier respiratory burden, lower blood eosinophil count, less emphysema but more bronchiectasis and pulmonary hypertension. Biomass exposure and previous tuberculosis were more common in these patients.