RT info:eu-repo/semantics/article
T1 A systems biology approach reveals a link between systemic cytokines and skeletal muscle energy metabolism in a rodent smoking model and human COPD
A1 Davidsen, Peter K.
A1 Herbert, Jhon M.
A1 Antczak, Kim
A1 Ferrer, Elisabet
A1 Peinado, Víctor I.
A1 González, Constancio
A1 Roca, Josep
A1 Egginton, Stuart
A1 Barberá, Joan A.
A1 Falciani, Francesco
K1 EPOC
AB Background: A relatively large percentage of patients with chronic obstructive pulmonary disease (COPD) developsystemic co-morbidities that affect prognosis, among which muscle wasting is particularly debilitating. Despitesignificant research effort, the pathophysiology of this important extrapulmonary manifestation is still unclear. A keyquestion that remains unanswered is to what extent systemic inflammatory mediators might play a role in thispathology.Cigarette smoke (CS) is the main risk factor for developing COPD and therefore animal models chronically exposedto CS have been proposed for mechanistic studies and biomarker discovery. Although mice have been successfullyused as a pre-clinical in vivo model to study the pulmonary effects of acute and chronic CS exposure, data suggestthat 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 skeletalmuscles from a Guinea pig rodent model exposed to CS and/or chronic hypoxia to COPD patients with musclewasting.Results: We show that guinea pigs exposed to long-term CS accurately reflect most of the transcriptional changesobserved in dysfunctional limb muscle of severe COPD patients when compared to matched controls. Using networkinference, we could then show that the expression profile in whole lung of genes encoding for soluble inflammatorymediators is informative of the molecular state of skeletal muscles in the guinea pig smoking model. Finally, we showthat CXCL10 and CXCL9, two of the candidate systemic cytokines identified using this pre-clinical model, are indeeddetected at significantly higher levels in serum of COPD patients, and that their serum protein level is inverselycorrelated 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 theregulation of central metabolism genes in skeletal muscles. On a methodological level, our work also shows that asystem level analysis of animal models of diseases can be very effective to generate clinically relevant hypothesis.
PB BioMed Central
SN 1756-994X
YR 2014
FD 2014
LK http://uvadoc.uva.es/handle/10324/6892
UL http://uvadoc.uva.es/handle/10324/6892
LA eng
NO Genome Medicine 2014, 6:59
NO Producción Científica
DS UVaDOC
RD 23-nov-2024