Rapid hemodilution induced by desmopressin after erythropoietin administration in humans

We have shown that treatment with desmopressin has a very effective hemodilution effect in healthy humans. These results led us to suggest the possible role of desmopressin to mask blood doping in sports. Based on our results, the World Anti-Doping Agency included the desmopressin in the 2011 List of Prohibited Substances and Methods. On this occasion, the aim of our study was to test the desmopressin-induced hemodilution after rHuEpo administration in humans. This was an intra-subject, crossover study in which five physically active males acted as their own controls. A basal blood sample was taken on their first visit to the laboratory. The next day, the subjects began the treatment. They received a subcutaneous rHuEpo injection three times/week for a two-week period. On the second visit to the laboratory, seventeen days later, a blood sample was taken. Thereafter, the subjects received an oral dose of 4.3 μg/kg of desmopressin and were instructed to ingest 1.5 liters of mineral water during the following fifteen minutes. Three hours after the water ingestion a second blood sample was obtained. The samples were analyzed for hematocrit (HCT), hemoglobin (Hb), reticulocytes (Ret%) and OFF Hr-Score. We found significantly higher HCT, Hb and Ret% levels after rHuEpo administration. Administration of desmopressin significantly decreased the HCT and Hb values but we did not find significant changes in Ret%. The values of the OFF Hr-Score also decreased after treatment with desmopressin. Desmopressin has a very effective hemodilution effect after rHuEpo administration and significantly modifies the hematological values measured by the anti-doping authorities to detect blood doping. We consider that these results reinforce the conclusions reported in our first study and confirm that desmopressin is a very effective masking agent for blood doping.This work was supported by grants SAF2008-00270; SAF2009-08334; BFU2007-65803/BFI; from the Spanish Ministry of Education and Science (MEC); PROMETEO/2010/074 from the Consellería de Educación de la Generalitat Valenciana. ISCIII2006-RED13-027 from the “Red Temática de investigación cooperativa en envejecimiento y fragilidad (RETICEF)”, EU Funded COSTB35 and DPS2008-06968 from Spanish Ministry of Innovation and Science. This study has been co-financed by FEDER funds from the European Union

The Oxygen Paradox, the French Paradox, and age-related diseases

open46openDavies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, Henry J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A.Davies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, HENRY J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A

Cell signaling involved in sarcopenia : role of oxidative stress and physical inactivity

La sarcopénie est considérée comme un syndrome gériatrique se caractérisant par une diminution de la masse musculaire qui en s’aggravant sera à l’origine d’une détérioration de la force musculaire et des performances physiques. La sarcopénie est évidemment imputable au processus de vieillissement, mais son développement peut être accéléré sous l’effet de facteurs pathologiques et comportementaux. Depuis un siècle à peine, le comportement de l’homme moderne, en matière d’activité physique, a radicalement changé avec un mode de vie de plus en plus inactif. Cette inactivité chronique est apparue trop soudainement pour permettre à notre génotype de s’adapter, et contribue ainsi à accélérer ledéveloppement de la sarcopénie. Néanmoins, des interrogations subsistent concernant les mécanismes cellulaires et moléculaires par lesquels l’inactivité physique favoriserait ce syndrome gériatrique. L’objectif de ce travail de thèse était donc de déterminer certains de ces mécanismes en se centrant tout particulièrement sur le rôle des espèces dérivées del’oxygène (ERDO). En s’appuyant sur différents modèles expérimentaux d’activité (entraînement en endurance) et d’inactivité (suspension par la queue) chez le rongeur, nos travaux ont mis en évidence le rôle essentiel de la surproduction chronique d’ERDO (qu’elle soit liée à l’âge et/ou l’inactivité) dans l’activation de certains facteurs de transcription et kinases redox-sensibles impliqués dans la sarcopénie (i.e. NF-κB, p38 MAPK). Nos travaux démontrent également que l’avance en âge (et probablement l’inactivité chronique) induit une perte de réactivité de PGC-1α, un facteur de transcription redoxsensible régulant un certain nombre de mécanismes cellulaires impliqués dans la sarcopénie. Cette perte deréactivité pourrait s’expliquer par la surproduction chronique d’ERDO dans le muscle âgéAging causes a progressive decline in skeletal muscle mass that may lead to decreased strength and functionality. The term sarcopenia is especially used to characterize this geriatric syndrome. Numerous conditions and behaviors are considered to accelerate the progression of sarcopenia such as chronic diseases, malnutrition and physical inactivity. In millennia past, and until recently, among hunter-gatherers and like populations, down through the ages, all people werephysically very active during early life and later in their everyday occupations. In contrast, nowadays, in Western populations, with relative abundance of food, a sedentary lifestyle is the rule. This radical change in lifestyle counteracts our active phenotype, and thus promotes the development of sarcopenia. Despite the recent advances in the etiology of sarcopenia, some questions remain concerning the cellular and molecular mechanisms by which the physical inactivity promotes sarcopenia. Consequently, the aim of this thesis was to determine some of these mechanisms, and more especially the role played by reactive oxygen species (ROS). We used different experimental rodent models of activity (physical training) and inactivity (hindlimb suspension) to achieve these objectives. Our research underlines the essential role of age or/and inactivity related chronic ROS overproduction in the activation of redox-sensitive transcription factors and kinases involved in sarcopenia (i.e. NF-κB and p38 MAPK). We also demonstrated that aging (and probably lifelong inactivity) induces a loss of PGC-1α reactivity, a key redox-sensitive transcription factor regulating some cellular mechanisms involved in sarcopenia. Chronic ROS overproduction in aged skeletal muscles may explain this loss of PGC-1α reactivit

Etude des voies de signalisation impliquées dans la sarcopénie : rôle du stress oxydant et de l'inactivité physique

Aging causes a progressive decline in skeletal muscle mass that may lead to decreased strength and functionality. The term sarcopenia is especially used to characterize this geriatric syndrome. Numerous conditions and behaviors are considered to accelerate the progression of sarcopenia such as chronic diseases, malnutrition and physical inactivity. In millennia past, and until recently, among hunter-gatherers and like populations, down through the ages, all people werephysically very active during early life and later in their everyday occupations. In contrast, nowadays, in Western populations, with relative abundance of food, a sedentary lifestyle is the rule. This radical change in lifestyle counteracts our active phenotype, and thus promotes the development of sarcopenia. Despite the recent advances in the etiology of sarcopenia, some questions remain concerning the cellular and molecular mechanisms by which the physical inactivity promotes sarcopenia. Consequently, the aim of this thesis was to determine some of these mechanisms, and more especially the role played by reactive oxygen species (ROS). We used different experimental rodent models of activity (physical training) and inactivity (hindlimb suspension) to achieve these objectives. Our research underlines the essential role of age or/and inactivity related chronic ROS overproduction in the activation of redox-sensitive transcription factors and kinases involved in sarcopenia (i.e. NF-κB and p38 MAPK). We also demonstrated that aging (and probably lifelong inactivity) induces a loss of PGC-1α reactivity, a key redox-sensitive transcription factor regulating some cellular mechanisms involved in sarcopenia. Chronic ROS overproduction in aged skeletal muscles may explain this loss of PGC-1α reactivityLa sarcopénie est considérée comme un syndrome gériatrique se caractérisant par une diminution de la masse musculaire qui en s’aggravant sera à l’origine d’une détérioration de la force musculaire et des performances physiques. La sarcopénie est évidemment imputable au processus de vieillissement, mais son développement peut être accéléré sous l’effet de facteurs pathologiques et comportementaux. Depuis un siècle à peine, le comportement de l’homme moderne, en matière d’activité physique, a radicalement changé avec un mode de vie de plus en plus inactif. Cette inactivité chronique est apparue trop soudainement pour permettre à notre génotype de s’adapter, et contribue ainsi à accélérer ledéveloppement de la sarcopénie. Néanmoins, des interrogations subsistent concernant les mécanismes cellulaires et moléculaires par lesquels l’inactivité physique favoriserait ce syndrome gériatrique. L’objectif de ce travail de thèse était donc de déterminer certains de ces mécanismes en se centrant tout particulièrement sur le rôle des espèces dérivées del’oxygène (ERDO). En s’appuyant sur différents modèles expérimentaux d’activité (entraînement en endurance) et d’inactivité (suspension par la queue) chez le rongeur, nos travaux ont mis en évidence le rôle essentiel de la surproduction chronique d’ERDO (qu’elle soit liée à l’âge et/ou l’inactivité) dans l’activation de certains facteurs de transcription et kinases redox-sensibles impliqués dans la sarcopénie (i.e. NF-κB, p38 MAPK). Nos travaux démontrent également que l’avance en âge (et probablement l’inactivité chronique) induit une perte de réactivité de PGC-1α, un facteur de transcription redoxsensible régulant un certain nombre de mécanismes cellulaires impliqués dans la sarcopénie. Cette perte deréactivité pourrait s’expliquer par la surproduction chronique d’ERDO dans le muscle âg

Mitochondrial fission and fusion in human diseases.

International audienceno abstrac

Coloration des fibres de réticuline sur tissu musculaire par la méthode de Gomori : intérêts pour l'étude de l'atrophie musculaire.

National audienceNo abstrac

OP17 - Natural antioxidants accelerate cachexia development in colon cancer

International audienceCancer cachexia is a multifactorial syndrome and a complex metabolic disorder, characterized by a continuous loss of muscle mass with or without depletion of adipose tissue. It manifests mainly in patients with advanced stages of colon cancer and accounts for more than 20% of mortality in total cancer patients. Muscle atrophy is one of the most relevant clinical events in cancer cachexia that negatively impact patient’s quality of life. Currently, it is well established and recognized that cachexia-induced muscle atrophy is intimately linked to oxidative stress (OS), since oxidative damages were increased in the skeletal muscle of cachectic patients and were positively correlated with muscle proteolysis. Thus, supplementation with natural antioxidants could be a valuable strategy to prevent the deterioration of patient’s quality of life and/or alleviate cachexia-related symptoms, like muscle atrophy. Herein, we tested the effectiveness of this strategy in a model of C26-tumor bearing mice. Five-week old Balb/c mice have received a subcutaneous injection of PBS or C26 cancer cells with or without daily supplementation with a cocktail of natural antioxidants. Venous blood and skeletal muscles were removed at 20-22 days after injection. We found that supplemented mice started to lose weight faster and died prematurely compared to no supplemented mice. Muscle atrophy occurred earlier in supplemented mice as evidenced by the decrease in fibers diameter, skeletal muscle weights and muscle endurance. These events were concomitant with an increase in systemic and muscular oxidative stress (e.g. carbonyls proteins, 4-HNE). Surprisingly, oxidative damage markers were decreased only in tumor of antioxidants-supplemented mice and were associated with a decrease in cell cycle inhibitors expression (e.g. p21), leading to tumor proliferation and progression. In line with recently published reports, our study support the evidence that antioxidants supplementation, if there is no need, could have deleterious consequences on health and well-bein

Physical inactivity, insulin resistanceand the oxidative-inflammatory loop

International audienceEpidemiological data indicate that physical inactivity, a main factor of global energetic imbalance, is involved in the worldwide epidemic of obesity and metabolic disorders such as insulin resistance. Although the complex pathogenesis of insulin resistance is not fully understood, literature data accumulated during the past decades clearly indicate that the activation of the oxidative-inflammatory loop plays a major role. By activating the oxidative-inflammatory loop in insulin-sensitive tissues, fat gain and adipose tissue dysfunction likely contribute to induce insulin resistance during chronic and prolonged physical inactivity. However, in the past years, evidence has emerged showing that early insulin resistance also occurs after very short-term exposure to physical inactivity (1-7 days) without any fat gain or energetic imbalance. The possible role of liver disturbances or endothelial dysfunction is suggested, but further studies are necessary to really conclude. Inactive skeletal muscle probably constitutes the primary triggering tissue for the development of early insulin resistance. In the present review, we discuss on the current knowledge about the effect of physical inactivity on whole-body and peripheral insulin sensitivityand how local inflammation and oxidative stress arising with physical inactivity could potentially induce insulin resistance. We assume that early muscle insulin resistance allows the excess nutrients to shift in the storage tissues to withstand starvation through energy storage. We also consider when chronic and prolonged, physical inactivity over an extended period of time is an underestimated contributor to pathological insulin resistance and hence indirectly to numerous chronic diseases

Antioxidant supplementation accelerates cachexia development by promoting tumor growth in C26 tumor-bearing mice

International audienceMore than 50% of patients with advanced stages of colon cancer suffer from progressive loss of skeletal muscle, called cachexia, resulting in reduced quality of life and shortened survival. It is becoming evident that reactive oxygen species (ROS) regulate pathways controlling skeletal muscle atrophy. Herein we tested the hypothesis that antioxidant supplementation could prevent skeletal muscle atrophy in a model of cachectic Colon 26 (C26) tumor-bearing mice. Seven-week-old BALB/c mice were subcutaneously inoculated with colon 26 (C26) cancer cells or PBS. Then C26-mice were daily gavaged during 22 days either with PBS (vehicle) or an antioxidant cocktail whose composition is close to that of commercial dietary antioxidant supplements (rich in catechins, quercetin and vitamin C). We found that antioxidants enhanced weight loss and caused premature death of mice. Antioxidants supplementation failed to prevent (i) the increase in plasma TNF-α levels and systemic oxidative damage, (ii) skeletal muscle atrophy and (iii) activation of the ubiquitin-proteasome system (MuRF-1, MAFbx and polyubiquitinated proteins). Accordingly, immunohistological staining for Ki-67 and the expression of cell cycle inhibitors demonstrated that tumor of supplemented mice developed faster with a concomitant decrease in oxidative damage. Previous studies have shown that the use of catechins and quercetin separately can improve the musculoskeletal function in cachectic animals. However, our results indicate that the combination of these antioxidants reduced survival and enhanced cachexia in C26-mice

Inactivity-induced oxidative stress: A central role in age-related sarcopenia?

International audienceno abstrac