Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung that generates progressive and largely poorly reversible airflow limitation 
. COPD represents a high burden on healthcare systems worldwide, since it is the fourth cause of death and its prevalence is expected to increase in forthcoming years 
The disease is primarily caused by the interplay between inhaled irritants, most frequently tobacco smoking but also environmental pollutants, and influenced by genetic susceptibility 
. In these patients, the disease results in shortness of breath and contributes to limitation of exercise tolerance, leading to a decrease in daily physical activities 
. The latter has a significant deleterious impact on both clinical outcomes and prognosis 
. Rehabilitation programs including skeletal muscle training and promotion of active lifestyles are recommended by all international clinical guidelines 
as pivotal elements in the therapeutic strategies for COPD, but they are insufficiently deployed. One of the reasons for this is that in a significant percentage of patients, skeletal muscle dysfunction and muscle wasting are hallmark systemic effects of COPD 
. Possibly linked with this, exercise-induced oxidative stress in COPD muscles is well documented and is likely to be an important mechanism driving tissue degeneration 
The role of systemic inflammation and myogenesis in skeletal muscle wasting are still a matter of controversy. However, recent studies have shown a reduction in the expression of myogenic genes in COPD muscles 
and a reduction in the ability to induce their expression in response to training in cachectic COPD patients 
, providing evidence for a deficiency in tissue remodelling. It has been proposed that lack of activation of myogenic pathways may be the result of the over-activation of the NF-kB pathway induced by systemic inflammatory signals generated by the lung 
. This hypothesis is supported by cell culture and animal experiments, but so far there has been little evidence that this mechanism is clinically relevant 
. Analysing a panel of muscle biopsies from normal and COPD individuals these authors showed that COPD muscles may be unable to activate NF-kB targets in response to physical training. Therefore, the mechanisms leading to skeletal muscle abnormalities in COPD and the relationship between muscle remodelling and oxidative damage are still a matter of intense research, and the extensive literature in this field is unable to support the development of effective predictive/preventive strategies.
The complex interplay of molecular pathways that are potentially involved in regulating muscle functionality makes a systems biology approach a desirable option. Such an approach aims to model the relationship between key molecular and physiological variables in healthy and diseased individuals to derive a testable hypothesis on the disease mechanism.
In this study, we hypothesized that skeletal muscle abnormalities in COPD may be the result of an imbalance in the physiological regulation of normal muscle homeostasis induced by systemic inflammatory mediators and chronic tissue hypoxia. In addition, we assume that the nature of such alteration might be reverse engineered by observing the statistical relationship between variables defining whole body physiology, systemic inflammation and muscle transcriptional state, with particular reference to cell bioenergetics and tissue remodelling functions. We based our analysis on a clinical study representing 12 healthy subjects and 18 age and sex-matched COPD patients, before and after undergoing an 8 weeks training program. In the latter category we included patients with preserved muscle mass (COPDN) and patients showing muscle wasting (COPDL).
We discovered that COPD muscles are characterized by a lack of correlation in expression of bioenergetic and tissue remodelling pathways, which included genes specifically involved in myogenesis. Our analysis suggests that failure to activate and coordinate these functions in response to training is associated with a general lack of activation of NF-kB targets, including many pro-inflammatory signals (e.g. IL-1β). We also discovered that expression of chromatin modification enzymes, known to control muscle differentiation and energy balance in other biological systems, is abnormal in COPD muscles and correlated with oxygen availability. This finding raises the possibility that an epigenetic mechanism triggered by tissue hypoxia may be the basis of skeletal muscle wasting in COPD.