Background. Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD) is not fully reversed by exercise training. Antioxidants are critical for muscle homeostasis and adaptation to training. However, COPD patients experience antioxidant deficits that worsen after training and might impact their muscle response to training. Nutritional antioxidant supplementation in combination with pulmonary rehabilitation (PR) would further improve muscle function, oxidative stress, and PR outcomes in COPD patients. Methods. Sixty-four COPD patients admitted to inpatient PR were randomized to receive 28 days of oral antioxidant supplementation targeting the previously observed deficits (PR antioxidant group; α-tocopherol: 30 mg/day, ascorbate: 180 mg/day, zinc gluconate: 15 mg/day, selenomethionine: 50 μg/day) or placebo (PR placebo group). PR consisted of 24 sessions of moderate-intensity exercise training. Changes in muscle endurance (primary outcome), oxidative stress, and PR outcomes were assessed. Results. Eighty-one percent of the patients (FEV1=58.9±20.0%pred) showed at least one nutritional antioxidant deficit. Training improved muscle endurance in the PR placebo group (+37.4±45.1%, p<0.001), without additional increase in the PR antioxidant group (-6.6±11.3%; p=0.56). Nevertheless, supplementation increased the α-tocopherol/γ-tocopherol ratio and selenium (+58±20%, p<0.001, and +16±5%, p<0.01, respectively), muscle strength (+11±3%, p<0.001), and serum total proteins (+7±2%, p<0.001), and it tended to increase the type I fiber proportion (+32±17%, p=0.07). The prevalence of muscle weakness decreased in the PR antioxidant group only, from 30.0 to 10.7% (p<0.05). Conclusions. While the primary outcome was not significantly improved, COPD patients demonstrate significant improvements of secondary outcomes (muscle strength and other training-refractory outcomes), suggesting a potential “add-on” effect of the nutritional antioxidant supplementation (vitamins C and E, zinc, and selenium) during PR. This trial is registered with NCT01942889.

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Among various strategies of exercise intensification proposed for the management of obesity and type 2 diabetes, endurance training remains a well recognized procedure. When targeted with exercise calorimetry at levels where lipid oxidation is maximal (LIPOXmax), it has been shown to improve mitochondrial respiration, blood glucose control and blood lipids, low grade inflammation and body composition, even at low weekly volume. We investigated in this study its long term effects over 3 years (3x45 min/week) compared to low fat diet without exercise (LFD) and a control group without any exercise or diet (C). 88 subjects that continued LIPOXmax training more than 1 year (23 men, 65 women, age=20-85 years, body mass index =23-48 kg/m 2 ) were compared to two matched groups (C and LFD). While C gained weight over this period, LFD and LIPOXmax group lose weight. Weight loss at 1 year was the same in exercise and diet group, but at 2 years and even more at 3 years there was a gradual weight regain in LFD so that results were better (p<0.01) in the exercise group who maintained weight loss in 80% of subjects. Average weight loss was -2,95 ± 0,37 kg after 3 months, -4,56 ± 0,68 kg after 1 year, -5,31 ± 1,26 kg at 2 years and -8,49 ± 2,39 kg at 3 years. The level at which LIPOXmax occurs is a predictor of weight loss at 1 year (r=-0,346 p<0,001) but not at 2 and 3 years. Weight loss at 3 months is a predictor of weight loss at 1 year (r=0,523 p<0,001) but not at 2 and 3 years. At 1 year subjects with LIPOX max in the lower quartile (<35% VO2max n=23) lose less weight than the others (-2.3 ± 0.98 vs -5.4 ± 0.83 p=0,05) but this difference vanishes over time. This study shows that this low intensity exercise training maintains its weight-reducing effect 3 years while diet is no longer efficient, and that this effect is initially related to muscular ability to oxidize lipids but that metabolic and behavioral adaptations have been further developed and contribute to a long lasting effect.By contrast, low intensity endurance, that promotes lipid oxidation, has been proposed since almost twenty years as a promising strategy against obesity [8][9][10][11][12] .When targeted with exercise calorimetry at levels where lipid oxidation is maximal (LIPOXmax), it has been shown to improve mitochondrial respiration [13], blood glucose control and blood lipids, low grade inflammation and body composition, even at low weekly volume [14]. Surprisingly, this approach generated less literature, perhaps because its weight-reducing effects over the short term, although significant, were not spectacular.However, its prolonged use has been shown to result in a sustained weight loss [15] which contrasts with the quite constant weight regain observed in almost all classical strategies [16]. In this study we aimed at determining over 3 years the kinetics of weight evolution of patients trained with low volumes of low intensity exercise targeted by exercise calorimetry in comparison with controls who did not change their lifestyle and class...

The proteolytic autophagy pathway is enhanced in the lower limb muscles of patients with chronic obstructive pulmonary disease (COPD). Reactive oxygen species (ROS) have been shown to regulate autophagy in the skeletal muscles, but the role of oxidative stress in the muscle autophagy of patients with COPD is unknown. We used cultured myoblasts and myotubes from the quadriceps of eight healthy subjects and twelve patients with COPD (FEV1% predicted: 102.0% and 32.0%, respectively; p < 0.0001). We compared the autophagosome formation, the expression of autophagy markers, and the autophagic flux in healthy subjects and the patients with COPD, and we evaluated the effects of the 3-methyladenine (3-MA) autophagy inhibitor on the atrophy of COPD myotubes. Autophagy was also assessed in COPD myotubes treated with an antioxidant molecule, ascorbic acid. Autophagosome formation was increased in COPD myoblasts and myotubes (p = 0.011; p < 0.001), and the LC3 2/LC3 1 ratio (p = 0.002), SQSTM1 mRNA and protein expression (p = 0.023; p = 0.007), BNIP3 expression (p = 0.031), and autophagic flux (p = 0.002) were higher in COPD myoblasts. Inhibition of autophagy with 3-MA increased the COPD myotube diameter (p < 0.001) to a level similar to the diameter of healthy subject myotubes. Treatment of COPD myotubes with ascorbic acid decreased ROS concentration (p < 0.001), ROS-induced protein carbonylation (p = 0.019), the LC3 2/LC3 1 ratio (p = 0.037), the expression of SQSTM1 (p < 0.001) and BNIP3 (p < 0.001), and increased the COPD myotube diameter (p < 0.001). Thus, autophagy signaling is enhanced in cultured COPD muscle cells. Furthermore, the oxidative stress level contributes to the regulation of autophagy, which is involved in the atrophy of COPD myotubes in vitro.