Abstract
Muscle dysfunction is one of the major comorbidity touching patients suffering from chronic obstructive pulmonary diseases (COPD). More than a physical handicap, muscle dysfunction is an indicator of survival in COPD patients. To restore functional capacities and effort tolerance, exercise training (ET) during a pulmonary rehabilitation program represents the best therapeutic approach. However, the beneficial effects induced by ET are limited both in intensity and time. This limitation is a major issue in the therapeutic strategy of COPD patients. One of the hypothesis that could explain these limitations is that the « Spill-over » of inflammatory molecules coming from the lung, into the systemic circulation, could instigates the deterioration of muscle microenvironment and limits the beneficial effects of ET.The objective of the thesis project is to study the role of the muscle cell microenvironment of COPD patients in the defective regeneration processes and to assess the implication of COPD microenvironment in the limited beneficial effects of ET.We have shown that autophagy, modulated by oxidative stress, was implicated in the alteration of COPD muscle cells in culture. We studied if the COPD microenvironment (COPD serum) could participate to the alterations of differentiation/regeneration processes of healthy human myoblasts. We then established an in vitro methodology allowing to study the effects of the COPD microenvironment on the healthy human myoblast differentiation. Using this approach, we have shown that severity of the disease affects the microenvironment composition, with an impact on the myoblast differentiation. It is probably due to an exhaustion of myogenic capacities by the COPD microenvironment. The ET seems to not be able to restore a suitable microenvironment composition for differentiation, promoting the expression of catabolism markers. We also observed that myoblasts from COPD patients exhibited defects of adaptation in response to an electrical stimulation (inducing similar adaptative responses to ET) suggesting that COPD myoblasts had an altered myogenic potential.This work suggests that COPD microenvironment drives some molecules that could leads to an exhaustion of myogenic potential of healthy human myoblasts. This effect of the microenvironment could finally lead to an altered muscle regeneration processes and limit the beneficial effects of ET in the COPD patient.