Muscle dysfunction in COPD : phenotypes, molecular mechanisms 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.
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.
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.
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.
- 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 :
- Pomiès P, Rodriguez J, Blaquière M, Sedraoui S, Gouzi F, Carnac G, Laoudj-Chenivesse D, Mercier J, Préfaut C, Hayot M .Reduced myotube diameter, atrophic signalling and elevated oxidative stress in cultured satellite cells from COPD patients. J Cell Mol Med. 2014 Oct 22. doi: 10.1111/jcmm.12390.
- Gouzi F, Abdellaoui A, Molinari N, Pinot E, Ayoub B, Laoudj-Chenivesse D, Cristol JP, Mercier J, Hayot M, Préfaut C. Fiber atrophy, oxidative stress, and oxidative fiber reduction are the attributes of different phenotypes in chronic obstructive pulmonary disease patients. J Appl Physiol (1985). 2013 Dec;115(12):1796-805.
- Gouzi F, Maury J, Molinari N, Pomiès P, Mercier J, Préfaut C, Hayot M.Reference values for vastus lateralis fiber size and type in healthy subjects over 40 years old: a systematic review and metaanalysis. J Appl Physiol (1985). 2013 Aug 1;115(3):346-54.
- Gouzi F, Préfaut C, Abdellaoui A, Roudier E, de Rigal P, Molinari N, Laoudj-Chenivesse D, Mercier J, Birot O, Hayot M. Blunted muscle angiogenic training-response in COPD patients versus sedentary controls. Eur Respir J. 2013 Apr;41(4):806-14.
- Gouzi F, Préfaut C, Abdellaoui A, Vuillemin A, Molinari N, Ninot G, Caris G, Hayot M.Evidence of an early physical activity reduction in chronic obstructive pulmonary disease patients. Arch Phys Med Rehabil. 2011 Oct;92(10):1611-1617.
- Abdellaoui A, Préfaut C, Gouzi F, Couillard A, Coisy-Quivy M, Hugon G, Molinari N, Lafontaine T, Jonquet O, Laoudj-Chenivesse D, Hayot M. Skeletal muscle effects of electrostimulation after COPD exacerbation: a pilot study. Eur Respir J. 2011 Oct;38(4):781-8.
- Hayot M, Rodriguez J, Vernus B, Carnac G, Jean E, Allen D, Goret L, Obert P, Candau R, Bonnieu A. Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuli. Mol Cell Endocrinol. 2011 Jan 30;332(1-2):38-47.
Collaborative Publications :
- Watz H, Pitta F, Rochester CL, Garcia-Aymerich J, ZuWallack R, Troosters T, Vaes AW, Puhan MA, Jehn M, Polkey MI, Vogiatzis I, Clini EM, Toth M, Gimeno-Santos E, Waschki B, Esteban C, Hayot M, Casaburi R, Porszasz J, McAuley E, Singh SJ, Langer D, Wouters EF, Magnussen H, Spruit MA. An official European Respiratory Society statement on physical activity in COPD. Eur Respir J. 2014 Dec;44(6):1521-37.
- Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigaré R, Dekhuijzen PN, Franssen F, Gayan-Ramirez G, Gea J, Gosker HR, Gosselink R, Hayot M, Hussain SN, Janssens W, Polkey MI, Roca J, Saey D, Schols AM, Spruit MA, Steiner M, Taivassalo T, Troosters T, Vogiatzis I, Wagner PD; ATS/ERS Ad Hoc Committee on Limb Muscle Dysfunction in COPD.An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014 May 1;189(9):e15-62.
- Makinson A, Hayot M, Eymard-Duvernay S, Quesnoy M, Raffi F, Thirard L, Bonnet F, Tattevin P, Abgrall S, Quantin X, Léna H, Bommart S, Reynes J, Le Moing V; the ANRS EP48 HIV CHEST Study Team. High prevalence of undiagnosed COPD in a cohort of HIV-infected smokers. Eur Respir J. 2014 Oct 16. pii: erj01549-2014.