Mécanismes moléculaires du contrôle de la masse musculaire sous l'action du b2-agoniste formotérol

Les b2-agonistes sont couramment utilisés pour prévenir et réduire les symptômes de l'asthme et de la bronchoconstriction induite par l'exercice. Mais, pris en quantités supérieures aux doses thérapeutiques, les b2-agonistes ont un effet anabolisant qui a été clairement démontré in vivo. Un certain nombre d acteurs sont mis en jeu dans la réponse biologique du tissu musculaire aux b2-agonistes. L un de ces acteurs est la voie de signalisation PI3K/Akt/mTOR, voie d initiation de la traduction, ayant un rôle majeur dans la synthèse protéique. Dans ce contexte, notre première étude avait pour objectif de déterminer la cinétique des événements moléculaires responsables de l hypertrophie du muscle squelettique de rat après administration de formotérol pendant 1 jour (J1), 3 jours (J3) et 10 jours (J10). Nous avons montré que l administration de formotérol induisait une hypertrophie musculaire à J3 et J10 associée à l activation transitoire de la voie de signalisation PI3K/Akt/mTOR (J1 et J3), et à une diminution de l expression de l E3 ubiquitine ligase MAFbx/Atrogin-1 (J3). La voie autophagie lysosome ne semblait pas être affectée. Ainsi, l ensemble de ces résultats suggère que l activation de la voie PI3K/Akt/mTOR est associée à la voie ubiquitine-protéasome mais pas à la voie autophagie-lysosome. La régulation transitoire de la voie PI3K/Akt/mTOR suggère que d autres voies de signalisation sont impliquées dans l hypertrophie musculaire induite par le formotérol. Le 007-AM, analogue de l AMPc, a été décrit comme pouvant stimuler la voie de signalisation PI3K/Akt/mTOR via l activation de la protéine Epac, suggérant que le 007-AM puisse constituer une molécule de substitution à l utilisation des b2-agonistes. Notre seconde étude avait pour but de déterminer si le 007-AM avait une action anabolisante sur le tissu musculaire, mais également de déterminer si la 007-AM était une molécule stable permettant d envisager son usage dans un cadre pharmacologique. L administration de 007-AM pendant 7 jours chez des souris n engendrait pas d hypertrophie musculaire. En revanche, in vitro sur cellules C2C12, le 007-AM activait la voie de signalisation PI3K/Akt/mTOR comme en témoignait l augmentation de la phosphorylation des protéines rpS6 et 4E-BP1. Nos résultats montraient également que le 007-AM était instable dans le plasma alors que son produit de dégradation, le 007 était plus stable. Pris ensembles, ces résultats suggèrent qu un traitement de 7 jours au 007-AM n est pas suffisant pour induire une hypertrophie musculaire et que l absence d hypertrophie musculaire pourrait provenir de l instabilité du 007-AM dans le plasma. Toutefois, des études supplémentaires seront nécessaires pour confirmer ces résultats2-agonists are traditionally used to prevent and reduce asthma symptoms and bronchoconstriction induced by exercise. Nevertheless, when administrated in vivo, at relatively high, far away from therapeutic doses, b2-agonists induce anabolic effects. Numerous actors are involved in biological response of the skeletal muscle, induced by b2-agonists. PI3K/Akt/mTOR signaling pathway, which initiates translation, is one of these actors. In this context, our first study aimed at determined the kinetic of molecular events responsible for skeletal muscle hypertrophy after 1 day (D1), 3 days (D3) and 10 days (D10) of formoterol administration. We have shown that formoterol administration induced skeletal muscle hypertrophy at D3 and D10 associated with a transient activation of PI3K/Akt/mTOR signaling pathway (D1 and D3), and, with a decrease in E3 ubiquitin ligase MAFbx/atrogin-1 expression (D3). The autophagy-lysosome pathway seems not to be regulated by formoterol administration. Taken together, these results suggest that PI3K/Akt/mTOR activation is temporally associated with the regulation of ubiquitin-proteasome but not the autophagy-lysosome pathway. The transient nature of the regulation of PI3K/Akt/mTOR signaling pathway also indicates that other unidentified pathways are probably activated to sustain the increase in skeletal muscle mass. Recently, 007-AM synthetic molecule has been described to stimulate PI3K/Akt/mTOR signaling pathway through Epac protein activation, suggesting that 007-AM could be an alternative to the use of b2-agonists. The purpose of our second study was to determine whether 007-AM had an anabolic action on skeletal muscle and if 007-AM was stable allowing considering its use in pharmacology. 007-AM administration for 7 days to mice does not lead to muscle hypertrophy. Nonetheless, in vitro on C2C12 cells, 007-AM activated PI3K/Akt/mTOR signaling pathway by increasing phosphorylation of rpS6 and 4E-BP1. Our results showed that contrary to 007, 007-AM was instable in plasma. Altogether, these results suggest that a 7-day 007-AM treatment is not sufficient to induce skeletal muscle hypertrophy. This lack of hypertrophy could be due to 007-AM instability in plasma. However, supplemental studies are needed to confirm these resultsST ETIENNE-Bib. électronique (422189901) / SudocSudocFranceF

Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington's disease models.

Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases

Mécanismes moléculaires du contrôle de la masse musculaire sous l'action du β2-agoniste formotérol

Β2-agonists are traditionally used to prevent and reduce asthma symptoms and bronchoconstriction induced by exercise. Nevertheless, when administrated in vivo, at relatively high, far away from therapeutic doses, β2-agonists induce anabolic effects. Numerous actors are involved in biological response of the skeletal muscle, induced by β2-agonists. PI3K/Akt/mTOR signaling pathway, which initiates translation, is one of these actors. In this context, our first study aimed at determined the kinetic of molecular events responsible for skeletal muscle hypertrophy after 1 day (D1), 3 days (D3) and 10 days (D10) of formoterol administration. We have shown that formoterol administration induced skeletal muscle hypertrophy at D3 and D10 associated with a transient activation of PI3K/Akt/mTOR signaling pathway (D1 and D3), and, with a decrease in E3 ubiquitin ligase MAFbx/atrogin-1 expression (D3). The autophagy-lysosome pathway seems not to be regulated by formoterol administration. Taken together, these results suggest that PI3K/Akt/mTOR activation is temporally associated with the regulation of ubiquitin-proteasome but not the autophagy-lysosome pathway. The transient nature of the regulation of PI3K/Akt/mTOR signaling pathway also indicates that other unidentified pathways are probably activated to sustain the increase in skeletal muscle mass. Recently, 007-AM synthetic molecule has been described to stimulate PI3K/Akt/mTOR signaling pathway through Epac protein activation, suggesting that 007-AM could be an alternative to the use of β2-agonists. The purpose of our second study was to determine whether 007-AM had an anabolic action on skeletal muscle and if 007-AM was stable allowing considering its use in pharmacology. 007-AM administration for 7 days to mice does not lead to muscle hypertrophy. Nonetheless, in vitro on C2C12 cells, 007-AM activated PI3K/Akt/mTOR signaling pathway by increasing phosphorylation of rpS6 and 4E-BP1. Our results showed that contrary to 007, 007-AM was instable in plasma. Altogether, these results suggest that a 7-day 007-AM treatment is not sufficient to induce skeletal muscle hypertrophy. This lack of hypertrophy could be due to 007-AM instability in plasma. However, supplemental studies are needed to confirm these resultsLes β2-agonistes sont couramment utilisés pour prévenir et réduire les symptômes de l'asthme et de la bronchoconstriction induite par l'exercice. Mais, pris en quantités supérieures aux doses thérapeutiques, les β2-agonistes ont un effet anabolisant qui a été clairement démontré in vivo. Un certain nombre d’acteurs sont mis en jeu dans la réponse biologique du tissu musculaire aux β2-agonistes. L’un de ces acteurs est la voie de signalisation PI3K/Akt/mTOR, voie d’initiation de la traduction, ayant un rôle majeur dans la synthèse protéique. Dans ce contexte, notre première étude avait pour objectif de déterminer la cinétique des événements moléculaires responsables de l’hypertrophie du muscle squelettique de rat après administration de formotérol pendant 1 jour (J1), 3 jours (J3) et 10 jours (J10). Nous avons montré que l’administration de formotérol induisait une hypertrophie musculaire à J3 et J10 associée à l’activation transitoire de la voie de signalisation PI3K/Akt/mTOR (J1 et J3), et à une diminution de l’expression de l’E3 ubiquitine ligase MAFbx/Atrogin-1 (J3). La voie autophagie lysosome ne semblait pas être affectée. Ainsi, l’ensemble de ces résultats suggère que l’activation de la voie PI3K/Akt/mTOR est associée à la voie ubiquitine-protéasome mais pas à la voie autophagie-lysosome. La régulation transitoire de la voie PI3K/Akt/mTOR suggère que d’autres voies de signalisation sont impliquées dans l’hypertrophie musculaire induite par le formotérol. Le 007-AM, analogue de l’AMPc, a été décrit comme pouvant stimuler la voie de signalisation PI3K/Akt/mTOR via l’activation de la protéine Epac, suggérant que le 007-AM puisse constituer une molécule de substitution à l’utilisation des β2-agonistes. Notre seconde étude avait pour but de déterminer si le 007-AM avait une action anabolisante sur le tissu musculaire, mais également de déterminer si la 007-AM était une molécule stable permettant d’envisager son usage dans un cadre pharmacologique. L’administration de 007-AM pendant 7 jours chez des souris n’engendrait pas d’hypertrophie musculaire. En revanche, in vitro sur cellules C2C12, le 007-AM activait la voie de signalisation PI3K/Akt/mTOR comme en témoignait l’augmentation de la phosphorylation des protéines rpS6 et 4E-BP1. Nos résultats montraient également que le 007-AM était instable dans le plasma alors que son produit de dégradation, le 007 était plus stable. Pris ensembles, ces résultats suggèrent qu’un traitement de 7 jours au 007-AM n’est pas suffisant pour induire une hypertrophie musculaire et que l’absence d’hypertrophie musculaire pourrait provenir de l’instabilité du 007-AM dans le plasma. Toutefois, des études supplémentaires seront nécessaires pour confirmer ces résultat

Molecular mechanisms controlling muscle mass under β2-agonist formoterol stimulations

Les β2-agonistes sont couramment utilisés pour prévenir et réduire les symptômes de l'asthme et de la bronchoconstriction induite par l'exercice. Mais, pris en quantités supérieures aux doses thérapeutiques, les β2-agonistes ont un effet anabolisant qui a été clairement démontré in vivo. Un certain nombre d’acteurs sont mis en jeu dans la réponse biologique du tissu musculaire aux β2-agonistes. L’un de ces acteurs est la voie de signalisation PI3K/Akt/mTOR, voie d’initiation de la traduction, ayant un rôle majeur dans la synthèse protéique. Dans ce contexte, notre première étude avait pour objectif de déterminer la cinétique des événements moléculaires responsables de l’hypertrophie du muscle squelettique de rat après administration de formotérol pendant 1 jour (J1), 3 jours (J3) et 10 jours (J10). Nous avons montré que l’administration de formotérol induisait une hypertrophie musculaire à J3 et J10 associée à l’activation transitoire de la voie de signalisation PI3K/Akt/mTOR (J1 et J3), et à une diminution de l’expression de l’E3 ubiquitine ligase MAFbx/Atrogin-1 (J3). La voie autophagie lysosome ne semblait pas être affectée. Ainsi, l’ensemble de ces résultats suggère que l’activation de la voie PI3K/Akt/mTOR est associée à la voie ubiquitine-protéasome mais pas à la voie autophagie-lysosome. La régulation transitoire de la voie PI3K/Akt/mTOR suggère que d’autres voies de signalisation sont impliquées dans l’hypertrophie musculaire induite par le formotérol. Le 007-AM, analogue de l’AMPc, a été décrit comme pouvant stimuler la voie de signalisation PI3K/Akt/mTOR via l’activation de la protéine Epac, suggérant que le 007-AM puisse constituer une molécule de substitution à l’utilisation des β2-agonistes. Notre seconde étude avait pour but de déterminer si le 007-AM avait une action anabolisante sur le tissu musculaire, mais également de déterminer si la 007-AM était une molécule stable permettant d’envisager son usage dans un cadre pharmacologique. L’administration de 007-AM pendant 7 jours chez des souris n’engendrait pas d’hypertrophie musculaire. En revanche, in vitro sur cellules C2C12, le 007-AM activait la voie de signalisation PI3K/Akt/mTOR comme en témoignait l’augmentation de la phosphorylation des protéines rpS6 et 4E-BP1. Nos résultats montraient également que le 007-AM était instable dans le plasma alors que son produit de dégradation, le 007 était plus stable. Pris ensembles, ces résultats suggèrent qu’un traitement de 7 jours au 007-AM n’est pas suffisant pour induire une hypertrophie musculaire et que l’absence d’hypertrophie musculaire pourrait provenir de l’instabilité du 007-AM dans le plasma. Toutefois, des études supplémentaires seront nécessaires pour confirmer ces résultatsΒ2-agonists are traditionally used to prevent and reduce asthma symptoms and bronchoconstriction induced by exercise. Nevertheless, when administrated in vivo, at relatively high, far away from therapeutic doses, β2-agonists induce anabolic effects. Numerous actors are involved in biological response of the skeletal muscle, induced by β2-agonists. PI3K/Akt/mTOR signaling pathway, which initiates translation, is one of these actors. In this context, our first study aimed at determined the kinetic of molecular events responsible for skeletal muscle hypertrophy after 1 day (D1), 3 days (D3) and 10 days (D10) of formoterol administration. We have shown that formoterol administration induced skeletal muscle hypertrophy at D3 and D10 associated with a transient activation of PI3K/Akt/mTOR signaling pathway (D1 and D3), and, with a decrease in E3 ubiquitin ligase MAFbx/atrogin-1 expression (D3). The autophagy-lysosome pathway seems not to be regulated by formoterol administration. Taken together, these results suggest that PI3K/Akt/mTOR activation is temporally associated with the regulation of ubiquitin-proteasome but not the autophagy-lysosome pathway. The transient nature of the regulation of PI3K/Akt/mTOR signaling pathway also indicates that other unidentified pathways are probably activated to sustain the increase in skeletal muscle mass. Recently, 007-AM synthetic molecule has been described to stimulate PI3K/Akt/mTOR signaling pathway through Epac protein activation, suggesting that 007-AM could be an alternative to the use of β2-agonists. The purpose of our second study was to determine whether 007-AM had an anabolic action on skeletal muscle and if 007-AM was stable allowing considering its use in pharmacology. 007-AM administration for 7 days to mice does not lead to muscle hypertrophy. Nonetheless, in vitro on C2C12 cells, 007-AM activated PI3K/Akt/mTOR signaling pathway by increasing phosphorylation of rpS6 and 4E-BP1. Our results showed that contrary to 007, 007-AM was instable in plasma. Altogether, these results suggest that a 7-day 007-AM treatment is not sufficient to induce skeletal muscle hypertrophy. This lack of hypertrophy could be due to 007-AM instability in plasma. However, supplemental studies are needed to confirm these result

Quand les marques utilisent les jeux vidéo pour faire leur pub :l'influence des règles du jeu pour légitimer la pratique d'advergaming

International audienc

Nutrient fluxes on an intertidal mudflat in Marennes-Oléron Bay, and influence of the emersion period

Fluxes of nutrients (NH4+, NO3-, PO43- and Si(OH)4) were studied on an intertidal mudflat in Marennes-Oléron Bay, France, at two different seasons and at different times of the emersion period. Fluxes through the sediment-water interface were both calculated from vertical profiles of nutrient concentration in pore-water (diffusive fluxes, JD) and measured in light and dark benthic mini-chambers (measured fluxes, J0). Results indicate that ammonia was mainly released in summer while nitrate was mainly taken up in late winter. This uptake from the overlying water was probably due to the coupling of nitrification-denitrification within the sediment. The J0/JD ratio further indicates that bioturbation likely enhanced ammonia release in summer. Concerning phosphate, the comparison of diffusive and measured fluxes suggests that PO43- could be assimilated by the biofilm in winter while it was released in summer at a high rate due to both bioturbation and desorption because of the relative anoxic conditions in summer. Silica was always released by the sediment, but at a higher rate in summer. Statistically significant differences in measured fluxes were detected in dark chambers at different times of low tide, thus suggesting a short-term variability of fluxes. Microphytobenthos preferred ammonia to nitrate, but assimilated nitrate when ammonia was not available. It also turned out that benthic cells could be limited in nitrogen during low tide in late winter. In summer, ammonia was not limiting and microphytobenthic activity significantly decreased the measured flux of NH4+ in the middle of low tide when its photosynthetic capacity was highest

Interacting effects of <I>Hydrobia ulvae</I> bioturbation and microphytobenthos on the erodibility of mudflat sediments

International audienceMicrophytobenthos-macrofauna sediment interactions and their effects on sediment erodability were examined in laboratory experiments. Sediment beds were manipulated in a tidal mesocosm to produce diatom mats in exponential or in stationary phases of development after 6, 8 or 11 d of culture. These sediment beds were used in flume experiments to investigate the influence of bioturbation by the gastropod Hydrobia ulvae on both sediment and pigment resuspension as a function of the physiological state of the microphytobenthic mats. In most experiments, only a surface layer was resuspended. A model was used to analyse in detail the contribution of each variable to this surface-layer erosion. Bioturbation was the major factor controlling resuspension, and its extent was influenced by sediment density and the growth stage of the microphytobenthos. The amount and extent of bioturbation is assumed to be influenced by sediment density and chlorophyll a content. Snail bioturbation can, in turn, influence the amount of microalgal resuspension. The quantity of pigment resuspended due to bioturbation increased by a factor of 15 when the diatom mats were in exponential growth stages. However, as the age of the mat increased, the influence of bioturbation on pigment resuspension declined. When the mats became senescent, Type I erosion occurred with erosion rates high enough to obscure any effects of bioturbation. To summarise, we assume that there are 2 causes of microphytobenthos resuspention, depending on the physiological state of the mat: (1) in the exponential phase, bioturbation substantially affects the resuspension of pigments which are present in the surface layer (the biogenic fluff layer) and (2) in the senescent phase, the increase in bed roughness and water content renders the mat fragile, leading to bed erosion

Coping styles in European sea bass: The link between boldness, stress response and neurogenesis

Coping styles consist of a coherent set of individual physiological and behavioral differences in stress responses that are consistent across time and context. Such consistent inter-individual differences in behavior have already been shown in European sea bass (Dicentrarchus labrax), but the associated mechanisms are still poorly understood. Here, we combine physiological measurements with individual behavioral responses in order to characterize coping styles in fish. Fish were tagged and placed in a tank for group risk-taking tests (GRT) at 8 months of age to evaluate boldness using the proxy latency of leaving a sheltered area towards an open area. A subsample of these fish were individually challenged 16 months later using an open field test (OFT), in which the boldness was assessed after being placed in a shelter within an open arena. Latency to exit the shelter, time spent in the shelter, and distance travelled were recorded for this purpose. The blood and brain were then collected to evaluate plasma cortisol concentration and neurotransmitter levels (dopamine, norepinephrine, serotonin, and related metabolites), as well as brain transcription of key genes involved in stress axis regulation (gr1, gr2, mr, crf), neurogenesis (neurod1, neurod2, pcna), and neuronal development (egr1). Fish acting bolder in the GRT were not necessarily those acting bolder in the OFT, highlighting the relatively low consistency across different types of tests performed with a 16-months interval. There was, however, a significant correlation between stress markers and boldness. Indeed, mRNA levels of mr, crf, gr2, egr1, and neurod2, as well as norepinephrine levels were higher in shy than bold fish, whereas brain serotonergic activity was lower in shy fish. Overall, our study highlights the fact that boldness was not consistent over time when testing context differed (group vs. alone). This is in agreement with previous literature suggesting that social context play a key role in boldness measurement and that the particular life history of each individual may account in shaping the personality fate of a fish

The influence of long emersion on biota, ammonium fluxes and nitrification in intertidal sediments of Marennes-Oléron Bay, France

International audienceA comparative study between waterlogged and reflooded intertidal sediments was undertaken in March and June 1999 through statistical analysis of selected sediment parameters (biota, salinity, O2, Eh), pool sizes and benthic fluxes of nutrients (NH4+, NO2−, NO3−) and nitrification rates. In March samples, absence of polychaetes and oligochaetes from upper sediment horizons were due to erosional events sweeping away surface sediments. Presence of richer annelid assemblages in June samples indicated more stable hydrodynamic conditions that favoured the development of benthic microalgae biofilms. Dewatering of sediments during a 3-day emersion period promoted a salinity rise on top layers, migration of pore water ions towards the sediment surface, and created sediment fissures that accelerated water exchange on reflooding. Reflooded and waterlogged sediment systems were comparable with respect to the release of NH4+ to overlying water but were different with respect to nitrification rates. Sediment-water NH4+ fluxes were higher (P=0.011) in March (3.3 mmol m−2 day−1) compared to June (1.4 mmol m−2 day−1) due to higher macrofauna biomasses and lower benthic microalgae concentrations in March samples. Potential nitrification rates (range from 19 to 60 mmol NO3− m−2 day−1) were not statistically different between March and June. A thinner oxic layer in reflooded compared with waterlogged systems reflects a decrease of O2 diffusion into sediment at high salinities which resulted in the fall of the actual nitrification rates (P<0.05). Our data suggest that long term dessication of intertidal sediments may depress the nitrification process at the ecosystem level