Team 3 / Theme 2

Muscle dysfunction in COPD : phenotypes, molecular Drapeau Françaismechanisms and responses to therapeutic approaches

Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disease in which peripheral muscle dysfunction is an important systemic consequence in terms of exercise intolerance, poor quality of life and reduced survival. We are currently developing translational studies to better assess the mechanisms involved in this muscle dysfunction and in the short-term responses to different therapeutic approaches. We are developing active regional, national and international collaborations, and we are currently participating to international boards on COPD statement on muscle function and physical activity. In future studies, we will also develop long-term assessment of muscle function of COPD patients. Our actual project focuses on 3 main research axes:

Objective 1 : To characterize the heterogeneity of response to rehabilitation and antioxidant supplementation.

Péroxydations lipidiques chez des patients BPCO (M)

Fig 1: Lipid peroxydations in COPD patients (µM)

We have started a clinical study to assess the effects of an anti-oxidant supplementation targeted on antioxidant deficits that we have observed in COPD patients, while they are doing a pulmonary rehabilitation. Preliminary results have shown that almost 90% of our patients present a pro/antioxidant imbalance but that this imbalance is not due to the same antioxidant deficit for each patient.

These heterogeneous antioxidant profiles highlight the fact that different responses to this intervention could be observed depending on the COPD phenotypes that may not all respond in a similar way. Our challenge will be therefore to determine what are the mechanisms by which antioxidants are effective in a given group or sub-group of patients in an effort to develop personalized antioxidant supplementation.

 

 

 

Objective 2 : To study the angiogenic responses to different regimen of exercise training in COPD.

Capillaires dans des coupes transversales de fibres musculaires BPCO (après REE)

Fig 2 :Capillaries in COPD cross sectionned muscle fibers (post-rehabilitation)

Based on our recent studies on angio-adaptation after a 4-week exercise training of moderate intensity, we have observed a blunted angiogenic response in COPD patients with lower improvement in capillary/fiber ratio and lower response in the pro/anti-angiogenic ratio (Gouzi et al., ERJ 2013). We will therefore test the hypothesis that the blunted response in COPD is not only a question of training intensity and/or training duration. We have therefore started a clinical trial in which several groups of patients and healthy subjects are submitted to a moderate- or high-intensity exercise training for 5 or 10 weeks. This study will provide data to assess the mechanisms of resistance to training at the cellular level for angiogenic response and for several others pathways, as we will obtain muscle biopsies from these subjects. We should therefore be able to determine if the blunted angiogenic response observed in COPD patients is a limit to the oxygen uptake of the COPD muscle leading to muscle dysfunction.

 

 Objective 3 : To assess the molecular mechanisms of muscle alteration using a cellular model.

BPCO myotubes en culture

Fig 3 :COPD myotubes in culture

Using a newly developed in vitro cellular model we have shown that cultured myotubes derived from COPD patients exhibit atrophy associated with elevated oxidative stress (Pomiès et al., JCMM 2014). To better study the involvement of oxidative stress in COPD muscle atrophy, we are currently assessing various pathways involved in muscle function and mass, such as muscle proteolysis, atrophy/hypertrophy imbalance signaling, autophagy process, and metabolic signaling.

Our general approach consists in studying the spontaneous expression of each pathway in a standard or specific cell environment, and the response to inhibitors (pharmacological or not) and to stimulation. In particular, we will test the beneficial effects of various antioxidant molecules on the oxidative stress and the atrophy of cultured COPD myotubes, knowing that if a molecule appears to improve the phenotype of COPD cultured cells, it would therefore be a potential candidate for a new clinical study with COPD patients.

 

Coordinators :

Hayot Maurice

Participants :

Passerieux émilie

Ayoub Bronia

 


 Collaborations :

  • Nelly Héraud, Philippe de Rigal et collaborateurs (Cliniques du Souffle du Groupe Fontalvie, France)
  • Olivier Birot (York University, Toronto, Canada)
  • Pierre Villeneuve (CIRAD, Montpellier, France)

Financial Support :

  • PHRC AREB-1 (CHRU Montpellier + Groupe Fontalvie)
  • µvascBPCO (APARD + CHRU Monpellier)

Major Publications :

Collaborative Publications :