title: Molecular mechanisms underlying COPD-muscle dysfunction unveiled through a systems medicine approach.
abstract: Skeletal muscle dysfunction is a systemic effect in one-third of patients with chronic obstructive pulmonary disease (COPD), characterized by high reactive-oxygen-species (ROS) production and abnormal endurance training-induced adaptive changes. However, the role of ROS in COPD remains unclear, not least because of the lack of appropriate tools to study multifactorial diseases.
  
  
  
  We describe a discrete model-driven method combining mechanistic and probabilistic approaches to decipher the role of ROS on the activity state of skeletal muscle regulatory network, assessed before and after an 8-week endurance training program in COPD patients and healthy subjects. In COPD, our computational analysis indicates abnormal training-induced regulatory responses leading to defective tissue remodeling and abnormal energy metabolism. Moreover, we identified tnf, insr, inha and myc as key regulators of abnormal training-induced adaptations in COPD. The tnf-insr pair was identified as a promising target for therapeutic interventions. Our work sheds new light on skeletal muscle dysfunction in COPD, opening new avenues for cost-effective therapies. It overcomes limitations of previous computational approaches showing high potential for the study of other multi-factorial diseases such as diabetes or cancer.
  
  
  
  jroca@clinic.ub.es or martacascante@ub.eduSupplementary information: Supplementary data are available at Bioinformatics online.
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, Institute of Biomedicine of University of Barcelona (IBUB) and IDIBAPS, Diagonal 645, Barcelona 08028, Spain.|Institut d' Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona 08028, Spain.|Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62, Szeged H-6726, Hungary.
authors: Igor
authors: I
authors: Marín de Mas
authors: Université Grenoble Alpes-CNRS, TIMC-IMAG UMR 5525, Faculté de Médecine, Grenoble 38041, France.
authors: Eric
authors: E
authors: Fanchon
authors: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62, Szeged H-6726, Hungary.
authors: Balázs
authors: B
authors: Papp
authors: Bioinformatics Core Facility, IDIBAPS-CEK, Hospital Clínic, University de Barcelona, Barcelona 08036, Spain.
authors: Susana
authors: S
authors: Kalko
authors: Institut d' Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona 08028, Spain.|Department of Pulmonary Medicine, Hospital Clínic, IDIBAPS, CIBERES, Universitat de Barcelona, Barcelona 08036, Spain.
authors: Josep
authors: J
authors: Roca
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, Institute of Biomedicine of University of Barcelona (IBUB) and IDIBAPS, Diagonal 645, Barcelona 08028, Spain.|Institut d' Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona 08028, Spain.
authors: Marta
authors: M
authors: Cascante
mesh_terms: D004734:Energy Metabolism; D015444:Exercise; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D049490:Systems Biology
chemical_list: D017382:Reactive Oxygen Species