High Intensity Interval Training and Muscle Adaptations During PR (MITOXITRAIN)

Mitochondrial Adaptations and Oxidative Stress With High Intensity Interval Training During Pulmonary Rehabilitation

Pulmonary rehabilitation (PR) is a validated treatment in patients with Chronic Obstructive Pulmonary Disease (COPD), improving exercise tolerance, quality of life and dyspnea. However, 20 to 30% of patients did not respond to PR and particularly those with chronic hypoxaemia. In most disabled patients, High Intensity Interval training (HIIT) is an alternative to perform exercise training with similar gain in exercise capacity than continuous exercise training. In patients with exercise-induced oxygen desaturation, the repetitions of hypoxia/resaturation phases during intermittent exercise could result in bursts of oxidative stress and induce positive or detrimental effect on mitochondrial function according to the importance in the oxidant stimulus. Few data have ascertained the benefit of HIIT on mitochondrial oxidative capacity (Vmax) in healthy subjects compared to continuous exercise training but no data are available in COPD patients with exercise-induced desaturation, and the change in oxidative stress in such training regimen. The investigators hypothesize that the repetitive bursts of oxidative stress and the improved antioxidant capacity in the course of the training sessions would stimulate mitochondrial adaptations to a larger extent after HIIT than continuous exercise training in severe COPD patients with hypoxemia. Moreover, they will assess the relationship between the change in oxidative stress in blood and in muscle. The clinical relevance of this study will be to ascertain the benefit and the safety of HITT in this subgroup of COPD patients in whom benefit of PR is often weak.

The investigators will conduct an open-label randomized controlled trial in 2 parallel groups of COPD patients referred for a pulmonary rehabilitation programme (PR). After inclusion the patients will be randomized in HIIT (IG) or continuous groups (CG). Two visits will be planned before and 2 immediately after completion of PR, with similar tests. A cycling endurance test performed until exhaustion CG: exercise at 75% of predetermined maximal workload (Wmax) IG: 1 min at Wmax followed with 1 min unloaded pedaling, up to a maximal duration of 30 minutes. During this test, oxygen consumption, minute ventilation, cardiac output (thoracic impedance), pulse oxygen saturation and muscle oxygen saturation (NIRS) will be recorded continuously. Markers of oxidative stress will be measured before and at the end of the cycling test (5 ml blood). The mitochondrial oxidative capacity of the quadriceps will be measured on a separate day. A 20 mg biopsy of the vastus lateralis will be obtained under local anaesthesia using a biopsy needle. Maximal mitochondrial oxygen consumption (Vmax) will be measured on fresh permeabilized fibers (10 mg) using high resolution respirometry (Oroboros®), and 10 mg will be frozen for determination of oxidative markers. Vmax was also determined non invasively by the recovery of muscle oxygen saturation (NIRS) during repetitive brief arterial occlusions (according to the method described by Ryan and coll). As part of PR, the participants will complete 20 sessions of exercise training (HIIT or continuous). The exercise intensity will be adapted weekly according to the participant's sensation. In the IG, the sessions will not exceed 40 min (20 min of active exercise).

High Intensity Interval training: 1 min at maximal workload followed by 1 min rest, repeated during a maximum of 40 min.

Low intensity continuous exercise training set at the level of the ventilatory threshold, lasting for a maximum of 40 min

muscle adaptations following intermittent high intensity interval exercise training and continuous low intensity exercise training

variation of maximal mitochondrial O2 consumption ( pmol O2.s-1.mg-1) ( with exercise training in both groups

variation with exercise training in both groups of blood oxidative stress, with a composite score obtained by the plasmatic levels of superoxide dismutase, gluthation peroxydase, xanthine oxidase, catalase and myeloperoxidase

variation of muscle oxidative capacity measured by NIRS(affinity constant, min-1) with exercise training in both groups

variations with exercise training in both groups of cardiac output (L.min-1) measurements during endurance cycling exercise

variations with exercise training in both groups of minute ventilation (L.min-1) measurements during endurance cycling exercise

variations with exercise training in both groups of tissue index oxygenation (TIO,%) measured by Near Infrared Spectroscopy during endurance cycling exercise

Inclusion Criteria: COPD diagnosed according to Global Obstructive Lung Diagnosis criteria; no exacerbation of COPD in the last month Referred for a pulmonary rehabilitation program Exercise-induced oxygen desaturation during a CardioPulmonary Exercise Test, defined as a decrease of oxygen saturation by pulse oximetry >4% from resting value. Written informed consent Negative pregnancy test whenever applicable. Exclusion Criteria: Acute exacerbation of COPD during the last 4 weeks Physical or psychological inability to perform exercise tests Life-threatening cardiac events contra-indicating exercise training Anticoagulant treatment (muscle biopsy) Pregnant or breastfeeding womenFemmes Subject with curator, deprived of freedoms or in safeguard of justice Non covered by the french social security system