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Título
A systems biology approach reveals a link between systemic cytokines and skeletal muscle energy metabolism in a rodent smoking model and human COPD
Autor
Año del Documento
2014
Editorial
BioMed Central
Descripción
Producción Científica
Documento Fuente
Genome Medicine 2014, 6:59
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.
Materias (normalizadas)
EPOC
ISSN
1756-994X
Revisión por pares
SI
Idioma
eng
Derechos
openAccess
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