A systems biology approach reveals a link between systemic cytokines and skeletal muscle energy metabolism in a rodent smoking model and human COPDReportar como inadecuado

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Genome Medicine

, 6:59

1. Genomics and epigenomics of disease


BackgroundA 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.

MethodsWe 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.

ResultsWe 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.

ConclusionsWe 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.

AbbreviationsBMIBody mass index

CHChronic hypoxia

COPDChronic obstructive pulmonary disease

CSCigarette smoke

CSCHChronic smoking and hypoxia combined

FDRFalse discovery rate

FFMIFat free mass index

GEOGene Expression Omnibus

KEGGKyoto Encyclopedia of Genes and Genomes

PCPrincipal component

PCAPrincipal component analysis

SAMSignificance Analysis of Microarray

Electronic supplementary materialThe online version of this article doi:10.1186-s13073-014-0059-5 contains supplementary material, which is available to authorized users.

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Autor: Peter K Davidsen - John M Herbert - Philipp Antczak - Kim Clarke - Elisabet Ferrer - Victor I Peinado - Constancio Gonza

Fuente: https://link.springer.com/

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