Allopurinol partially prevents disuse muscle atrophy in mice and humans.

Disuse muscle wasting will likely affect everyone in his or her lifetime in response to pathologies such as joint immobilization, inactivity or bed rest. There are no good therapies to treat it. We previously found that allopurinol, a drug widely used to treat gout, protects muscle damage after exhaustive exercise and results in functional gains in old individuals. Thus, we decided to test its effect in the prevention of soleus muscle atrophy after two weeks of hindlimb unloading in mice, and lower leg immobilization following ankle sprain in humans (EudraCT: 2011-003541-17). Our results show that allopurinol partially protects against muscle atrophy in both mice and humans. The protective effect of allopurinol is similar to that of resistance exercise which is the best-known way to prevent muscle mass loss in disuse human models. We report that allopurinol protects against the loss of muscle mass by inhibiting the expression of ubiquitin ligases. Our results suggest that the ubiquitin-proteasome pathway is an appropriate therapeutic target to inhibit muscle wasting and emphasizes the role of allopurinol as a non-hormonal intervention to treat disuse muscle atrophy.

Exercise training combined with antioxidant supplementation prevents the antiproliferative activity of their single treatment in prostate cancer through inhibition of redox adaptation.

In preclinical models, exercise training (ET) or pomegranate juice (PJ) prevents prostate cancer progression. Here, we hypothesized that physical exercise combined with antioxidants could induce synergistic effects through oxidative stress modulation. Forty male Copenhagen rats with prostate tumors were divided into four groups: control, PJ, ET, and PJ+ET. Rats from the PJ group consumed 750 µl of PJ daily, rats from the ET group ran on a treadmill 5 days per week, and PJ+ET rats received the combined treatment. Each week, tumor growth was evaluated. After 4 weeks of treatment, the rats were euthanized and blood, muscles, and tumors were collected. Tumor Ki67, extracellular signal-regulated kinase (ERK) activation, Bcl-2 expression, and enzymatic and nonenzymatic antioxidant defenses, as well as oxidative stress markers (oxidized base, lipid peroxidation, protein carbonylation), were measured. PJ or ET significantly decreased prostate tumor proliferation (Ki67 staining, p<0.05) through the modulation of ERK phosphorylation, whereas the combination of treatments did not limit cancer progression. PJ significantly reduced Bcl-2 expression in tumors (p<0.05) and the combination of PJ and ET prevented this effect. PJ or ET increased enzymatic antioxidant defenses in muscle, PJ increased nonenzymatic antioxidant defenses in plasma and whole blood. In addition, PJ reduced TBARS and 8-oxodGuo levels in tumors as well as ET (p<0.05), whereas protein carbonyl levels were not affected by these two strategies. Paradoxically, association of PJ+ET did not increase antioxidant defenses and no reduction in oxidative stress markers was induced. Loading cancer cells with antioxidants blunts the positive effects of ET and interferes with important reactive oxygen species-mediated physiological processes such as antioxidant adaptations.

Inhibition of xanthine oxidase by allopurinol prevents skeletal muscle atrophy: role of p38 MAPKinase and E3 ubiquitin ligases.

Alterations in muscle play an important role in common diseases and conditions. Reactive oxygen species (ROS) are generated during hindlimb unloading due, at least in part, to the activation of xanthine oxidase (XO). The major aim of this study was to determine the mechanism by which XO activation causes unloading-induced muscle atrophy in rats, and its possible prevention by allopurinol, a well-known inhibitor of this enzyme. For this purpose we studied one of the main redox sensitive signalling cascades involved in skeletal muscle atrophy i.e. p38 MAPKinase, and the expression of two well known muscle specific E3 ubiquitin ligases involved in proteolysis, the Muscle atrophy F-Box (MAFbx; also known as atrogin-1) and Muscle RING (Really Interesting New Gene) Finger-1 (MuRF-1). We found that hindlimb unloading induced a significant increase in XO activity and in the protein expression of the antioxidant enzymes CuZnSOD and Catalase in skeletal muscle. The most relevant new fact reported in this paper is that inhibition of XO with allopurinol, a drug widely used in clinical practice, prevents soleus muscle atrophy by ~20% after hindlimb unloading. This was associated with the inhibition of the p38 MAPK-MAFbx pathway. Our data suggest that XO was involved in the loss of muscle mass via the activation of the p38MAPK-MAFbx pathway in unloaded muscle atrophy. Thus, allopurinol may have clinical benefits to combat skeletal muscle atrophy in bedridden, astronauts, sarcopenic, and cachexic patients.

Nutritional and plasmatic antioxidant vitamins status of ultra endurance athletes.

OBJECTIVE: The "Marathon des Sables" (MDS) is a competition known to induce oxidative stress. Antioxidant vitamins prevent exercise-induced oxidative damages. The purpose of this study was to evaluate daily intake and plasma level of the main antioxidant vitamins (alpha-tocopherol, vitamin C, beta-carotene and retinol) in 19 male athletes who participated in this competition. METHODS: Data collected before the beginning of the competition included daily dietary intake using a 7-day food record and plasma biochemical measurements (alpha-tocopherol, vitamin C, beta-carotene and retinol). RESULTS: First, total energy intake was obviously lower than the energetic intake usually observed in well-trained endurance athletes. Second, antioxidant vitamins intake was also insufficient. Indeed, the intake was lower than the French Dietary Reference Intakes (DRI) for this population in 18 subjects for vitamin E and 6 subjects for vitamin C, beta-carotene and Retinol Equivalent. As a significant relationship was found between total energy intake and the intake of vitamin E (r = 0.73; p < 0.001) and vitamin C (r = 0.78; p < 0.001), the low total energy intake contributed partially to the insufficient antioxidant vitamins intake. The dietary questionnaire analysis also revealed a low intake of vegetable oils, fruits and vegetables. However, plasma concentrations of these antioxidant vitamins were similar to the literature data observed in athletes. CONCLUSION: This study evidenced obvious insufficient energy intake in ultra endurance athletes associated with a low antioxidant vitamin intake.

Multivitamin-mineral supplementation prevents lipid peroxidation during "the Marathon des Sables".

OBJECTIVE: We investigated the effect of a moderate mutivitamin and mineral supplementation containing mainly vitamin C (150.0 mg.day(-1)), vitamin E (24.0 mg.day(-1)) and beta-carotene (4.8 mg.day(-1)) prior to and during an extreme running competition -the Marathon des Sables (MDS)- that consisted of six long races in the desert. METHODS: Seventeen athletes participated in our double blind, placebo-controlled study. Blood samples were collected prior to the supplementation i.e. three weeks before the competition (D-21), two days prior to the MDS (D-2), after the third race (D3) and at the end of the competition (D7). Erythrocyte antioxidant enzyme activity (glutathione peroxidase (GPx), superoxide dismutase (SOD)), erythrocyte glutathione level (GSH), plasma non-enzymatic antioxidant status (uric acid, vitamin C, alpha-tocopherol, retinol, beta-carotene), markers of plasma lipid peroxidation (thiobarbituric reactive substances (TBARS)), reactive carbonyl derivatives (RCD) and membrane damage (creatine kinase and lactate dehydrogenase activities) were measured. RESULTS: In both groups, GSH levels, uric acid levels and membrane damage significantly increased during the competition while SOD activity significantly decreased. In Supplemented group, plasma alpha-tocopherol, beta-carotene and retinol levels significantly increased after three weeks of supplementing. In contrast to Placebo group, alpha-tocopherol, vitamin C and retinol levels were significantly affected by the competition in Supplemented group. Moreover, no increase in TBARS was observed in Supplemented group during the competition, whereas TBARS significantly increased at D3 in the placebo group. CONCLUSION: The moderate multivitamin-mineral supplementation prevented the transient increase in TBARS levels during this extreme competition.

Extreme running competition decreases blood antioxidant defense capacity.

OBJECTIVE: We tested whether an extreme running competition ("Marathon of Sands") might alter the blood's enzymatic and non-enzymatic antioxidant status in 6 well-trained athletes. METHODS: The Marathon of Sands is a competition consisting of six long duration races in the desert in which the athletes carry their own food. Blood samples were collected from an antecubital vein while the athletes were at rest before the competition and then again 72 hours after. Erythrocyte antioxidant enzyme activity (glutathione peroxidase, superoxide dismutase), erythrocyte glutathione level, plasma non-enzymatic status (vitamin C, alpha-tocopherol, retinol, beta-carotene and carotenoids) and plasma lipid peroxidation marker (TBARS) were measured. RESULTS: The Marathon of Sands induced a significant alteration of the blood antioxidant defense capacity. Indeed, 72 hours after the race, significant decreases were recorded in erythrocyte superoxide dismutase activity and in plasma concentrations of retinol, beta-carotene and other carotenoids. These changes were associated with a concomitant increase in erythrocyte glutathione and in plasma TBARS levels. CONCLUSION: This study indicated that such extreme competition induced an imbalance between oxidant and antioxidant protection.

Plasma glucose, insulin and catecholamine responses to a Wingate test in physically active women and men.

The influence of gender on the glucose response to exercise remains contradictory. Moreover, to our knowledge, the glucoregulatory responses to anaerobic sprint exercise have only been studied in male subjects. Hence, the aim of the present study was to compare glucoregulatory metabolic (glucose and lactate) and hormonal (insulin, catecholamines and estradiol only in women) responses to a 30-s Wingate test, in physically active students. Eight women [19.8 (0.7) years] and eight men [22.0 (0.6) years] participated in a 30-s Wingate test on a bicycle ergometer. Plasma glucose, insulin, and catecholamine concentrations were determined at rest, at the end of both the warm-up and the exercise period and during the recovery (5, 10, 20, and 30 min). Results showed that the plasma glucose increase in response to a 30-s Wingate test was significantly higher in women than in men [0.99 (0.15) versus 0.33 (0.20) mmol l(-1) respectively, P<0.05]. Plasma insulin concentrations peaked at 10 min post-exercise and the increase between this time of recovery and the end of the warm-up was also significantly higher in women than in men [14.7 (2.9) versus 2.3 (1.9) pmol l(-1) respectively, P<0.05]. However, there was no gender difference concerning the catecholamine response. The study indicates a gender-related difference in post-exercise plasma glucose and insulin responses after a supramaximal exercise.