title: A systems biology approach reveals a link between systemic cytokines and skeletal muscle energy metabolism in a rodent smoking model and human COPD.
abstract: BACKGROUND
  A relatively large percentage of patients with chronic obstructive pulmonary disease (COPD) develop systemic co-morbidities that affect prognosis, among which muscle wasting is particularly debilitating. Despite significant research effort, the pathophysiology of this important extrapulmonary manifestation is still unclear. A key question that remains unanswered is to what extent systemic inflammatory mediators might play a role in this pathology. Cigarette smoke (CS) is the main risk factor for developing COPD and therefore animal models chronically exposed to CS have been proposed for mechanistic studies and biomarker discovery. Although mice have been successfully used as a pre-clinical in vivo model to study the pulmonary effects of acute and chronic CS exposure, data suggest that they may be inadequate models for studying the effects of CS on peripheral muscle function. In contrast, recent findings indicate that the guinea pig model (Cavia porcellus) may better mimic muscle wasting.
  
  
  METHODS
  We have used a systems biology approach to compare the transcriptional profile of hindlimb skeletal muscles from a Guinea pig rodent model exposed to CS and/or chronic hypoxia to COPD patients with muscle wasting.
  
  
  RESULTS
  We show that guinea pigs exposed to long-term CS accurately reflect most of the transcriptional changes observed in dysfunctional limb muscle of severe COPD patients when compared to matched controls. Using network inference, we could then show that the expression profile in whole lung of genes encoding for soluble inflammatory mediators is informative of the molecular state of skeletal muscles in the guinea pig smoking model. Finally, we show that CXCL10 and CXCL9, two of the candidate systemic cytokines identified using this pre-clinical model, are indeed detected at significantly higher levels in serum of COPD patients, and that their serum protein level is inversely correlated with the expression of aerobic energy metabolism genes in skeletal muscle.
  
  
  CONCLUSIONS
  We conclude that CXCL10 and CXCL9 are promising candidate inflammatory signals linked to the regulation of central metabolism genes in skeletal muscles. On a methodological level, our work also shows that a system level analysis of animal models of diseases can be very effective to generate clinically relevant hypothesis.
authors.affiliation: Centre for Computational Biology and Modelling, Institute for Integrative Biology, University of Liverpool, Crown Street, L69 7ZB Liverpool, UK ; School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Davidsen
authors.affiliation: Centre for Computational Biology and Modelling, Institute for Integrative Biology, University of Liverpool, Crown Street, L69 7ZB Liverpool, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Herbert
authors.affiliation: Centre for Computational Biology and Modelling, Institute for Integrative Biology, University of Liverpool, Crown Street, L69 7ZB Liverpool, UK.
authors.forename: Philipp
authors.initials: P
authors.lastname: Antczak
authors.affiliation: Centre for Computational Biology and Modelling, Institute for Integrative Biology, University of Liverpool, Crown Street, L69 7ZB Liverpool, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Clarke
authors.affiliation: Department of Pulmonary Medicine, Hospital Clinic, University of Barcelona, Barcelona, Spain ; Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ferrer
authors.affiliation: Department of Pulmonary Medicine, Hospital Clinic, University of Barcelona, Barcelona, Spain ; Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain ; Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Barcelona, Spain.
authors.forename: Victor I
authors.initials: VI
authors.lastname: Peinado
authors.affiliation: Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Barcelona, Spain ; Department of Biochemistry and Molecular Biology and Physiology, University of Valladolid, Valladolid, Spain.
authors.forename: Constancio
authors.initials: C
authors.lastname: Gonzalez
authors.affiliation: Department of Pulmonary Medicine, Hospital Clinic, University of Barcelona, Barcelona, Spain ; Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain ; Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Roca
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Egginton
authors.affiliation: Department of Pulmonary Medicine, Hospital Clinic, University of Barcelona, Barcelona, Spain ; Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain ; Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Barcelona, Spain.
authors.forename: Joan A
authors.initials: JA
authors.lastname: Barberá
authors.affiliation: Centre for Computational Biology and Modelling, Institute for Integrative Biology, University of Liverpool, Crown Street, L69 7ZB Liverpool, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Falciani