Dataset Information

A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease.

ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients.

SUBMITTER: Turan N

PROVIDER: S-EPMC3164707 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease.

Turan Nil N Kalko Susana S Stincone Anna A Clarke Kim K Sabah Ayesha A Howlett Katherine K Curnow S John SJ Rodriguez Diego A DA Cascante Marta M O'Neill Laura L Egginton Stuart S Roca Josep J Falciani Francesco F

PLoS computational biology 20110901 9

Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and p ...[more]

PMID: 21909251

Similar Datasets

Project description:BackgroundPulmonary rehabilitation (PR) is a cornerstone in the management of chronic obstructive pulmonary disease (COPD), targeting skeletal muscle to improve functional performance. However, there is substantial inter-individual variability in the effect of PR on functional performance, which cannot be fully accounted for by generic phenotypic factors. We performed an unbiased integrative analysis of the skeletal muscle molecular responses to PR in COPD patients and comprehensively characterized their baseline pulmonary and physical function, body composition, blood profile, comorbidities, and medication use.MethodsMusculus vastus lateralis biopsies were obtained from 51 COPD patients (age 64 ± 1 years, sex 73% men, FEV1 , 34 (26-41) %pred.) before and after 4 weeks high-intensity supervised in-patient PR. Muscle molecular markers were grouped by network-constrained clustering, and their relative changes in expression values-assessed by qPCR and western blot-were reduced to process scores by principal component analysis. Patients were subsequently clustered based on these process scores. Pre-PR and post-PR functional performance was assessed by incremental cycle ergometry and 6 min walking test (6MWT).ResultsEight molecular processes were discerned by network-constrained hierarchical clustering of the skeletal muscle molecular rehabilitation responses. Based on the resulting process scores, four clusters of patients were identified by hierarchical cluster analysis. Two major patient clusters differed in PR-induced autophagy (P < 0.001), myogenesis (P = 0.014), glucocorticoid signalling (P < 0.001), and oxidative metabolism regulation (P < 0.001), with Cluster 1 (C1; n = 29) overall displaying a more pronounced change in marker expression than Cluster 2 (C2; n = 16). General baseline characteristics did not differ between clusters. Following PR, both 6 min walking distance (+26.5 ± 8.3 m, P = 0.003) and peak load on the cycle ergometer test (+9.7 ± 1.9 W, P < 0.001) were improved. However, the functional improvement was more pronounced in C1, as a higher percentage of patients exceeded the minimal clinically important difference in peak workload (61 vs. 21%, P = 0.022) and both peak workload and 6 min walking test (52 vs. 8%, P = 0.008) upon PR.ConclusionsWe identified patient groups with distinct skeletal muscle molecular responses to rehabilitation, associated with differences in functional improvements upon PR.

Project description:ObjectiveSkeletal 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.MethodsA 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.ResultsCompared 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, Fe2+, 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.ConclusionCS 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.

Dataset Information

A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease.

Publications

A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets