These studies investigated the impact of intensity and body temperature on performance and cardiovascular regulation during high intensity and prolonged exercise. In study 1, polyphenol antioxidant supplementation proved to have no effect on exercise performance and related variables (gross efficiency, perceived exertion, maximal power) during exercise in the heat. Furthermore, there were no differences between the cardiovascular or thermoregulatory responses between control and antioxidant treatments. Study 2 utilized an integrative approach to investigate a classic topic in exercise physiology, namely, is the cardiac output to oxygen consumption relationship linear across a wide range of exercise intensities? The slope of the CO vs. VO2 relationship was significantly reduced from 70 to 100% of VO2max when compared to the slope from 40 to 70% of VO2max (2.0 ± 0.4 vs. 4.4 ± 0.3 l/min, p = 0.025). This finding, in combination with the plateau and eventual reduction in stroke volume at high intensity exercise compared to moderate intensity exercise (146.0 ± 16.6 vs. 138.5 ± 14.9 ml/beat, p = 0.015), argues in favor of a cardiac limitation to high intensity exercise. This study also showed that the pattern of oxygen extraction at the whole body level (arterial venous O2 difference) and the muscle level (deoxygenated hemoglobin) is not similar and that muscle specific differences exist regarding oxygen extraction. Study 3 determined that hyperthermia (elevation of skin temperature by 4.3°C and core temperature by 0.8°C) did not reduce SV independent of the increase in HR. Even under conditions of moderate hyperthermia the reduction in SV is due to the increase in HR and temporally unrelated to increases in cutaneous blood flow. In summary, antioxidant supplementation had no effect on performance, cardiovascular, or thermoregulatory responses to exercise in the heat in well trained subjects. High intensity exercise is associated with a reduced rate of increase in the CO vs. VO2 relationship. Finally, hyperthermia does not reduce SV during exercise when HR is maintained at normal levels. / text

Physical activity of moderate intensity and duration leads to healthy biological adaptations in humans. However, very intense and prolonged exercise may induce disruption in redox balance, potentially increasing oxidative stress. In addition, exposure to environmental heat stress and associated hyperthermia further increases oxidative stress and may induce the expression of heat shock proteins. However, antioxidant supplementation is believed to minimise the effect of oxidative stress and may therefore help reduce or limit the heat shock response to exercise heat stress. The first study (Chapter 4) examined whether exertional heat illness (EHI) casualties among military recruits may exhibit greater disturbances in redox balance following exercise compared to non-EHI controls. Nine (n=9) recruits were identified as having suspected EHI during the Loaded March (LM) on day 1, with a peak mean (SD) body core temperature of 40.1 (0.5) °C. Fifteen (n=15) recruits were identified as having suspected EHI during the Log Race (LR) on day 2, with a peak mean (SD) body core temperature of 39.7 (0.5) °C. A further twenty-one (n=21) recruits, which successfully finished both LM and LR events, were treated as controls (CON). Interestingly, the plasma antioxidant concentration was significantly elevated from pre to post-exercise (p < 0.001) for EHI and CON groups, during both LM and LR events, with no changes on lipid peroxide protein carbonyl concentrations. These data suggest there is no increase in lipid peroxide or protein carbonyl level damage in response to intense hyperthermic military exercise, regardless of acute heat illness. It is possible that military training augments the body's defence capabilities, thus reducing oxidative stress and damage induced by free radical production. To date there is a scarcity of data examining the effects of acute intake of antioxidant supplements on oxidative stress and heat shock response during continuous exercise in a hot environment. Hence, the aims of the second study (Chapter 5) were to examine the effects of acute ingestion of Quercetin (Q), Quercetin + vitamin C (QC) or placebo (P) 14 hours before, 2 hours before and every 20 minutes during trials on oxidative stress and heat shock response. In this randomised, crossover study 10 recreationally active males (age 21±2 y, V̇ O2max 54.9±8.4 ml.kg.min-1) completed three running trials at 70% V̇ O2max for 60 minutes in the heat (33.0±0.3°C; 28.5±1.8% relative humidity). Exercise heat stress significantly elevated plasma quercetin (p=0.02), antioxidant power (FRAP) (p < 0.001),plasma heat shock protein 70 (HSP70) (p=0.009) and plasma heat shock protein 90α(HSP90α) (p < 0.001) over time, but no differences were detected between trials. Also, no changes were observed in protein carbonyl concentration. Acute intake of quercetin significantly increased the level of plasma quercetin however, this did not affect the plasma antioxidant capacity or heat shock response to exercise heat stress. The increases in plasma HSP70 and HSP90α concentrations might act as supplementary antioxidants, reducing the oxidative damage reflected in the absence of changes in protein carbonyl. Exercise heat stress is effective in inducing both intracellular HSP70 (muscle and peripheral blood mononuclear cell (PBMC)) and extracellular HSP70 (plasma) concentrations. Thus, the third study (Chapter 6) tested the hypothesis that this acute quercetin supplementation would induce similar trends in plasma HSP70 and intracellular HSP70 concentrations 2 days following exercise heat stress. In this randomised, crossover study, 9 recreationally active males (age 22±2y, V̇ O2max 50.3±3.3ml.kg.min-1) completed three running trials at 70% V̇ O2max for 60 minutes in the heat (32.9±0.3°C; 28.3±1.2% relative humidity). This study demonstrated that there is no positive relationship between both intracellular of HSP70 (muscle and PBMC) and plasma HSP70 (eHSP70) 2 days following exercise heat stress. These data suggest that the release of eHSP70 could originate from others tissue or cells. Additionally, the absence of differences between trials in the expression of muscle HSP70, PBMC HSP70 and plasma HSP70 might indicate it is implausible that quercetin might inhibit the expression of HSP70 in plasma, muscle and PBMC 2 days following the exercise heat stress stimulus. Overall, the results from this thesis emphasise that the hyperthermia experienced in response to exercise and environmental heat stress could potentially influence the human redox response and heat shock response. Besides, there is reasonable evidence that acute quercetin co-ingestion with vitamin C has the potential to improve the bioavailability and bioactive effects of quercetin, however, the effects of quercetin supplementation in reducing oxidative stress in response to exercise heat stress remains to be elucidated. In addition, the anti-oxidative ability of acute ingestion of quercetin to suppress the intracellular and extracellular heat shock response remains uncertain and worthy for further investigation.

Les espèces réactives de l’oxygène (ERO) contrôlent plusieurs aspects de la carcinogenèse, étant donné leur capacité àpromouvoir la prolifération mais aussi à induire la sénescence et l’apoptose. Dans les stades avancés de cancer, les EROpeuvent également participer au développement de l’atrophie musculaire, engendrant une détérioration de la qualité de viedes patients. L’activité physique (AP), connue pour augmenter les défenses antioxydants de l’organisme et lasupplémentation en antioxydants sont considérées comme deux stratégies susceptibles de moduler la croissance tumorale, d’améliorer la performance physique et de réduire les effets secondaires liés à la maladie et aux traitements anticancéreux. Néanmoins, plusieurs questions restent aujourd’hui sans réponse. En effet, bien que l’AP puisse réduire la progression du cancer du sein, du colon et de la prostate, son impact sur les cancers se développant au sein du muscle (ex : le liposarcome), donc soumis aux contractions musculaires répétées, reste méconnu. En utilisant des approches in vivo et in vitro, nous avons démontré que maintenir une AP régulière accélère la croissance du liposarcome intramusculaire, probablement, via la réduction des taux circulants d’insuline et l’inhibition de la voie « P38 MAPK-P21 ». Pour les patients ne pouvant pas pratiquer d’AP, la consommation d’antioxydants pourrait être un moyen de réduire les ERO tumorales et musculaires et ainsi être prometteuse. Toutefois, les études actuelles restent très controversées. Nos travaux ont montré dans un modèle murin de cachexie cancéreuse que des doses nutritionnelles d’un produit antioxydant commercialisé en France, étaient suffisantes pour accélérer la croissance de la tumeur colique, favoriser la perte de masse corporelle totale et musculaire et engendrer la mort prématurée des souris. L’ensemble de nos résultats suggère que la pratique d’AP et la consommation en antioxydants peuvent induire des effets différents selon le type de tumeur et leur implantation, nécessitant une prise en charge individualisée des patients. En effet, (1) les patients atteints d’un LS intramusculaire devraient éviter de pratiquer une AP durant la période préopératoire mais ces résultats doivent être confirmés par une étude clinique, (2) les patients avec un stade avancé de cancer devraient être vigilants quant à l’utilisation de suppléments antioxydants ; une telle pratique pouvant avoir des répercussions dangereuses sur leur santé. / Reactive oxygen species (ROS) control several aspects of carcinogenesis as they can either promote tumor growth andprogression or senescence and apoptosis. In advanced stages of cancer, ROS can also drive the development of other cancerrelated complications like, muscle wasting. Physical activity (PA) and antioxidant supplementation have been proposed as two adjuvant strategies to better control tumor growth, ameliorate performance and alleviate secondary symptoms related to cancer itself or to the heavy anticancer therapies. However, several issues remain to be elucidated. First of all, although PA could reduce colon, breast and prostate cancer growth and progression, its impact remains unknown on orthotopic intramuscular tumors like liposarcoma, which directly affect the musculoskeletal apparatus and reduce physical function. Secondly, given the limitedness of PA application in some advanced stages of cancer, patients may increase their dependency on nutritional and antioxidant complements as an alternative strategy, but such practice has spark a lot of polemic and inconsistent results. In this thesis, we have addressed the effectiveness of PA and antioxidants in two distinct animal models of cancer. Using in vivo and in vitro approaches, we found that voluntary PA accelerated the growth of intramuscular liposarcoma tumors and exacerbated skeletal muscle dysfunction, mainly, by decreasing circulating insulin levels and the subsequent activation of the tumor suppressor pathway “P38 MAPK-P21”. We also demonstrated that nutritional doses of commercial antioxidants enhanced colon tumor growth, total body/skeletal muscle weight loss and caused premature death of mice. Such mechanism was due to selective changes in oxidative damage profiles, which decreased in tumor but increased in skeletal muscle, in a way driving tumor growth and skeletal muscle wasting/dysfunction. Clinically, it seems that (1) patients with intramuscular liposarcoma may, at least, not increase their levels of PA or undergo hospital-supervised exercise program, during the preoperative period; until the confirmation of our findings with clinical data and (2) patients with advanced stages of cancer must be very careful against the use of antioxidants as it could lifethreatening. Accordingly, health agencies in France, Europe and USA prohibit the use of synthetic antioxidant supplements without dietary counseling by a cancer patient’s physician and/or nutritionist.