Implication des céramides dans l'atrophie musculaire

Le muscle squelettique fait preuve d'une remarquable plasticité en réponse aux changements physiologiques, comme l activité physique, et aux situations pathologiques. Il subit notamment une atrophie sévère lors de la cachexie qui accompagne diverses pathologies chroniques comme le cancer, le SIDA, etc. L atrophie musculaire est aussiune composante de la sarcopénie qui survient lors du vieillissement normal, et se caractérise par un déclin de la force et de la masse musculaire. L'atrophie musculaire, qui entraîne une augmentation de la mortalité et diminue l efficacité des traitements, constitue donc un problème de santé majeur.La fonte musculaire se caractérise par une altération de l équilibre entre synthèse et dégradation protéiques dans les fibres adultes. Des taux particulièrement élevés de cytokines circulantes, dont le TNFa, qui affectent l homéostasie du muscle via différentes voies de signalisation, semblent être à l origine de l'atrophie. Les mécanismes de la réponse atrophique musculaire à ces taux circulants élevés sont cependant mal définis. Le TNFa a des effets complexes. Il peut activer de multiples voies de signalisation, parmi lesquelles l'induction de la synthèse de sphingolipides, et plus particulièrement de céramides, par la voie de novo et par l'activation des sphingomyélinases. Au niveau musculaire, les céramides sont connus pour leurs effets sur la signalisation de l'insuline, sur l'apoptose et sur la différenciation myogénique. Par contre, leur implication dans le cadre de l'atrophie n'avait jamais été prise en compte. L objectif de ce travail a été dans un premier temps de démontrer le rôle des céramides dans l atrophie. Dans un deuxième temps, nous avons caractérisé la voie de signalisation par laquelle l augmentation intramusculaire de céramide induite par le TNFa aboutit à une chute de la synthèse protéique, couplée à une augmentation de la protéolyse. Dans ce but, nous avons mis au point des modèles in vitro d'atrophie, impliquant des myotubes traités par des concentrations physiologiques de TNF . Nous avons en parallèle étudié un modèle in vivo de cachexie induite chez la souris par l'implantation d un adénocarcinome C26. L analyse des sphingolipides nous a permis de montrer l augmentation des taux de céramides concomitante à l atrophie générée in vitro et in vivo. Le rôle des céramides dans l atrophie a été démontré par l effet protecteur des inhibiteurs de leur synthèse, dans les modèles in vitro et in vivo. Nous montrons de plus dans un modèle in vitro que les effets atrophiques des céramides sont dus à l inhibition de la voie de signalisation Phospholipase D/mTOR/Akt. Nos résultats nous ont permis de prouver le rôle des sphingolipides dans le contrôle de l homéostasie protéique du muscle. La modulation du métabolisme des sphingolipides apparaît donc comme une nouvelle cible thérapeutique prometteuse dans le traitement de la perte musculaire associée à diverses pathologies.Skeletal muscle demonstrated a remarkable plasticity in response to physiological changes, such as physical activity, and pathological situations. He suffered such severe atrophy during cachexia that accompanies various pathologies such as cancer, AIDS, etc.. Muscle atrophy is also a component of sarcopenia that occurs during normal aging, and is characterized by a decline in strength and muscle mass. Muscle atrophy, which leads to increased mortality and decreased treatment efficacy, thus constitutes a health problem majeur.La muscle wasting is characterized by an impaired balance between protein synthesis and degradation in adult fibers. Particularly high levels of circulating cytokines, including TNF, which affect muscle homeostasis via different signaling pathways appear to be the cause of atrophy. Mechanisms of muscle atrophy response to these elevated circulating levels are however unclear. TNFa has complex effects. It may activate multiple signaling pathways, including the induction of the synthesis of sphingolipids, especially ceramides, for the de novo pathway and the activation of sphingomyelinases. In muscle, ceramides are known for their effects on insulin signaling on apoptosis and myogenic differentiation. By cons, their involvement in the context of atrophy was never taken into account. The objective of this work was firstly to demonstrate the role of ceramides in atrophy. In a second step, we characterized the signaling pathway by which increased intramuscular ceramide induced by TNF leads to a fall in protein synthesis, coupled with an increase in proteolysis. For this purpose, we have developed in vitro models of atrophy involving myotubes treated with physiological concentrations of TNF . We studied in parallel an in vivo model of cachexia induced in mice by implantation of adenocarcinoma C26. Analysis of sphingolipids we showed increased levels of ceramide concomitant atrophy generated in vitro and in vivo. The role of ceramide in atrophy has been demonstrated by the protective effect of inhibitors of their synthesis in the in vitro and in vivo. We show further in an in vitro model that atrophic effects of ceramides are due to inhibition of phospholipase D signaling pathway / mTOR / Akt. Our results allowed us to prove the role of sphingolipids in the homeostatic control of muscle protein. Modulation of sphingolipid metabolism appears to be a promising new therapeutic target in the treatment of muscle wasting associated with various pathologies.VILLEURBANNE-DOC'INSA LYON (692662301) / SudocVILLEURBANNE-DOC'INSA-Bib. elec. (692669901) / SudocSudocFranceF

TNF-α- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism

Additional filesInternational audienceUNLABELLED: ABSTRACT: BACKGROUND: Muscle atrophy associated with various pathophysiological conditions represents a major health problem, because of its contribution to the deterioration of patient status and its effect on mortality. Although the involvement of pro-inflammatory cytokines in this process is well recognized, the role of sphingolipid metabolism alterations induced by the cytokines has received little attention. RESULTS: We addressed this question both in vitro using differentiated myotubes treated with TNF-α, and in vivo in a murine model of tumor-induced cachexia. Myotube atrophy induced by TNF-α was accompanied by a substantial increase in cell ceramide levels, and could be mimicked by the addition of exogenous ceramides. It could be prevented by the addition of ceramide-synthesis inhibitors that targeted either the de novo pathway (myriocin), or the sphingomyelinases (GW4869 and 3-O-methylsphingomyelin). In the presence of TNF-α, ceramide-synthesis inhibitors significantly increased protein synthesis and decreased proteolysis. In parallel, they lowered the expression of both the Atrogin-1 and LC3b genes, involved in muscle protein degradation by proteasome and in autophagic proteolysis, respectively, and increased the proportion of inactive, phosphorylated Foxo3 transcription factor. Furthermore, these inhibitors increased the expression and/or phosphorylation levels of key factors regulating protein metabolism, including phospholipase D, an activator of mammalian target of rapamycin (mTOR), and the mTOR substrates S6K1 and Akt. In vivo, C26 carcinoma implantation induced a substantial increase in muscle ceramide, together with drastic muscle atrophy. Treatment of the animals with myriocin reduced the expression of the atrogenes Foxo3 and Atrogin-1, and partially protected muscle tissue from atrophy. CONCLUSIONS: Ceramide accumulation induced by TNF-α or tumor development participates in the mechanism of muscle-cell atrophy, and sphingolipid metabolism is a logical target for pharmacological or nutritional interventions aiming at preserving muscle mass in pathological situations

Nutraceutical properties of chestnut flours: beneficial effects on skeletal muscle atrophy

Plants contain a wide range of non-nutritive phytochemicals, many of which have protective or preventive properties for human diseases. The aim of the present work has been to investigate the nutraceutical properties of sweet chestnut flour extracts obtained from fruits collected from 7 geographic areas of Tuscany (Italy), and their ability in modulating skeletal muscle atrophy. We found that the cultivars from different geographic areas are characterized by the composition and quantity of various nutrients and specific bioactive components, such as tocopherols, polyphenols and sphingolipids. The nutraceutical properties of chestnut sweet flours have been evaluated in C2C12 myotubes induced to atrophy by serum deprivation or dexamethasone. We found that the pretreatment with both total extracts of tocopherols and sphingolipids is able to counterbalance cell atrophy, reducing the decrease in myotube size and myonuclei number, and attenuating protein degradation and the increase in expression of MAFbx/atrogin-1 (a muscle-specific atrophy marker). By contrast, polyphenol extracts were not able to prevent atrophy. Since we also found that γ-tocopherol is the major form of tocopherol in sweet flour and its content differs depending on the procedure of sweet flour preparation, the mechanisms by which γ-tocopherol as well as sphingolipids affect skeletal muscle cell atrophy have been also investigated. This is the first evidence that chestnut sweet flour is a natural source of specific bioactive components with a relevant role in the prevention of cell degeneration and maintenance of skeletal muscle mass, opening important implications in designing appropriate nutritional therapeutic approaches to skeletal muscle atrophy

Lipid modulation of skeletal muscle mass and function

Loss of skeletal muscle mass is a characteristic feature of various pathologies including cancer, diabetes, and obesity, as well as being a general feature of ageing. However, the processes underlying its pathogenesis are not fully understood and may involve multiple factors. Importantly, there is growing evidence which supports a role for fatty acids and their derived lipid intermediates in the regulation of skeletal muscle mass and function. In this review, we discuss evidence pertaining to those pathways which are involved in the reduction, increase and/or preservation of skeletal muscle mass by such lipids under various pathological conditions, and highlight studies investigating how these processes may be influenced by dietary supplementation as well as genetic and/or pharmacological intervention

Omega-3 fatty acid EPA improves regenerative capacity of mouse skeletal muscle cells exposed to saturated fat and inflammation

© 2016 The Author(s) Sarcopenic obesity is characterised by high fat mass, low muscle mass and an elevated inflammatory environmental milieu. We therefore investigated the effects of elevated inflammatory cytokine TNF-α (aging/obesity) and saturated fatty acid, palmitate (obesity) on skeletal muscle cells in the presence/absence of EPA, a-3 polyunsaturated fatty acid with proposed anti-inflammatory, anti-obesity activities. In the present study we show that palmitate was lipotoxic, inducing high levels of cell death and blocking myotube formation. Cell death under these conditions was associated with increased caspase activity, suppression of differentiation, reductions in both creatine kinase activity and gene expression of myogenic factors; IGF-II, IGFBP-5, MyoD and myogenin. However, inhibition of caspase activity via administration of Z-VDVAD-FMK (caspase-2), Z-DEVD-FMK (caspase-3) and ZIETD-KMK (caspase 8) was without effect on cell death. By contrast, lipotoxicity associated with elevated palmitate was reduced with the MEK inhibitor PD98059, indicating palmitate induced cell death was MAPK mediated. These lipotoxic conditions were further exacerbated in the presence of inflammation via TNF-α co-administration. Addition of EPA under cytotoxic stress (TNF-α) was shown to partially rescue differentiation with enhanced myotube formation being associated with increased MyoD, myogenin, IGF-II and IGFBP-5 expression. EPA had little impact on the cell death phenotype observed in lipotoxic conditions but did show benefit in restoring differentiation under lipotoxic plus cytotoxic conditions. Under these conditions Id3 (inhibitor of differentiation) gene expression was inversely linked with survival rates, potentially indicating a novel role of EPA and Id3 in the regulation of apoptosis in lipotoxic/cytotoxic conditions. Additionally, signalling studies indicated the combination of lipo- and cyto-toxic effects on the muscle cells acted through ceramide, JNK and MAPK pathways and blocking these pathways using PD98059 (MEK inhibitor) and Fumonisin B1 (ceramide inhibitor) significantly reduced levels of cell death. These findings highlight novel pathways associated with in vitro models of lipotoxicity (palmitate-mediated) and cytotoxicity (inflammatory cytokine mediated) in the potential targeting of molecular modulators of sarcopenic obesity

Implication des céramides dans l'atrophie musculaire

Skeletal muscle demonstrated a remarkable plasticity in response to physiological changes, such as physical activity, and pathological situations. He suffered such severe atrophy during cachexia that accompanies various pathologies such as cancer, AIDS, etc.. Muscle atrophy is also a component of sarcopenia that occurs during normal aging, and is characterized by a decline in strength and muscle mass. Muscle atrophy, which leads to increased mortality and decreased treatment efficacy, thus constitutes a health problem majeur.La muscle wasting is characterized by an impaired balance between protein synthesis and degradation in adult fibers. Particularly high levels of circulating cytokines, including TNF, which affect muscle homeostasis via different signaling pathways appear to be the cause of atrophy. Mechanisms of muscle atrophy response to these elevated circulating levels are however unclear. TNFa has complex effects. It may activate multiple signaling pathways, including the induction of the synthesis of sphingolipids, especially ceramides, for the de novo pathway and the activation of sphingomyelinases. In muscle, ceramides are known for their effects on insulin signaling on apoptosis and myogenic differentiation. By cons, their involvement in the context of atrophy was never taken into account. The objective of this work was firstly to demonstrate the role of ceramides in atrophy. In a second step, we characterized the signaling pathway by which increased intramuscular ceramide induced by TNF leads to a fall in protein synthesis, coupled with an increase in proteolysis. For this purpose, we have developed in vitro models of atrophy involving myotubes treated with physiological concentrations of TNF . We studied in parallel an in vivo model of cachexia induced in mice by implantation of adenocarcinoma C26. Analysis of sphingolipids we showed increased levels of ceramide concomitant atrophy generated in vitro and in vivo. The role of ceramide in atrophy has been demonstrated by the protective effect of inhibitors of their synthesis in the in vitro and in vivo. We show further in an in vitro model that atrophic effects of ceramides are due to inhibition of phospholipase D signaling pathway / mTOR / Akt. Our results allowed us to prove the role of sphingolipids in the homeostatic control of muscle protein. Modulation of sphingolipid metabolism appears to be a promising new therapeutic target in the treatment of muscle wasting associated with various pathologies.Le muscle squelettique fait preuve d'une remarquable plasticité en réponse aux changements physiologiques, comme l’activité physique, et aux situations pathologiques. Il subit notamment une atrophie sévère lors de la cachexie qui accompagne diverses pathologies chroniques comme le cancer, le SIDA, etc. L’atrophie musculaire est aussi une composante de la sarcopénie qui survient lors du vieillissement normal, et se caractérise par un déclin de la force et de la masse musculaire. L'atrophie musculaire, qui entraîne une augmentation de la mortalité et diminue l’efficacité des traitements, constitue donc un problème de santé majeur.La fonte musculaire se caractérise par une altération de l’équilibre entre synthèse et dégradation protéiques dans les fibres adultes. Des taux particulièrement élevés de cytokines circulantes, dont le TNFα, qui affectent l’homéostasie du muscle via différentes voies de signalisation, semblent être à l’origine de l'atrophie. Les mécanismes de la réponse atrophique musculaire à ces taux circulants élevés sont cependant mal définis. Le TNFα a des effets complexes. Il peut activer de multiples voies de signalisation, parmi lesquelles l'induction de la synthèse de sphingolipides, et plus particulièrement de céramides, par la voie de novo et par l'activation des sphingomyélinases. Au niveau musculaire, les céramides sont connus pour leurs effets sur la signalisation de l'insuline, sur l'apoptose et sur la différenciation myogénique. Par contre, leur implication dans le cadre de l'atrophie n'avait jamais été prise en compte. L’objectif de ce travail a été dans un premier temps de démontrer le rôle des céramides dans l’atrophie. Dans un deuxième temps, nous avons caractérisé la voie de signalisation par laquelle l’augmentation intramusculaire de céramide induite par le TNFα aboutit à une chute de la synthèse protéique, couplée à une augmentation de la protéolyse. Dans ce but, nous avons mis au point des modèles in vitro d'atrophie, impliquant des myotubes traités par des concentrations physiologiques de TNF. Nous avons en parallèle étudié un modèle in vivo de cachexie induite chez la souris par l'implantation d’un adénocarcinome C26. L’analyse des sphingolipides nous a permis de montrer l’augmentation des taux de céramides concomitante à l’atrophie générée in vitro et in vivo. Le rôle des céramides dans l’atrophie a été démontré par l’effet protecteur des inhibiteurs de leur synthèse, dans les modèles in vitro et in vivo. Nous montrons de plus dans un modèle in vitro que les effets atrophiques des céramides sont dus à l’inhibition de la voie de signalisation Phospholipase D/mTOR/Akt. Nos résultats nous ont permis de prouver le rôle des sphingolipides dans le contrôle de l’homéostasie protéique du muscle. La modulation du métabolisme des sphingolipides apparaît donc comme une nouvelle cible thérapeutique prometteuse dans le traitement de la perte musculaire associée à diverses pathologies

Involvement of ceramides in muscle atrophy

Skeletal muscle demonstrated a remarkable plasticity in response to physiological changes, such as physical activity, and pathological situations. He suffered such severe atrophy during cachexia that accompanies various pathologies such as cancer, AIDS, etc.. Muscle atrophy is also a component of sarcopenia that occurs during normal aging, and is characterized by a decline in strength and muscle mass. Muscle atrophy, which leads to increased mortality and decreased treatment efficacy, thus constitutes a health problem majeur.La muscle wasting is characterized by an impaired balance between protein synthesis and degradation in adult fibers. Particularly high levels of circulating cytokines, including TNF, which affect muscle homeostasis via different signaling pathways appear to be the cause of atrophy. Mechanisms of muscle atrophy response to these elevated circulating levels are however unclear. TNFa has complex effects. It may activate multiple signaling pathways, including the induction of the synthesis of sphingolipids, especially ceramides, for the de novo pathway and the activation of sphingomyelinases. In muscle, ceramides are known for their effects on insulin signaling on apoptosis and myogenic differentiation. By cons, their involvement in the context of atrophy was never taken into account. The objective of this work was firstly to demonstrate the role of ceramides in atrophy. In a second step, we characterized the signaling pathway by which increased intramuscular ceramide induced by TNF leads to a fall in protein synthesis, coupled with an increase in proteolysis. For this purpose, we have developed in vitro models of atrophy involving myotubes treated with physiological concentrations of TNF . We studied in parallel an in vivo model of cachexia induced in mice by implantation of adenocarcinoma C26. Analysis of sphingolipids we showed increased levels of ceramide concomitant atrophy generated in vitro and in vivo. The role of ceramide in atrophy has been demonstrated by the protective effect of inhibitors of their synthesis in the in vitro and in vivo. We show further in an in vitro model that atrophic effects of ceramides are due to inhibition of phospholipase D signaling pathway / mTOR / Akt. Our results allowed us to prove the role of sphingolipids in the homeostatic control of muscle protein. Modulation of sphingolipid metabolism appears to be a promising new therapeutic target in the treatment of muscle wasting associated with various pathologies.Le muscle squelettique fait preuve d'une remarquable plasticité en réponse aux changements physiologiques, comme l’activité physique, et aux situations pathologiques. Il subit notamment une atrophie sévère lors de la cachexie qui accompagne diverses pathologies chroniques comme le cancer, le SIDA, etc. L’atrophie musculaire est aussi une composante de la sarcopénie qui survient lors du vieillissement normal, et se caractérise par un déclin de la force et de la masse musculaire. L'atrophie musculaire, qui entraîne une augmentation de la mortalité et diminue l’efficacité des traitements, constitue donc un problème de santé majeur.La fonte musculaire se caractérise par une altération de l’équilibre entre synthèse et dégradation protéiques dans les fibres adultes. Des taux particulièrement élevés de cytokines circulantes, dont le TNFα, qui affectent l’homéostasie du muscle via différentes voies de signalisation, semblent être à l’origine de l'atrophie. Les mécanismes de la réponse atrophique musculaire à ces taux circulants élevés sont cependant mal définis. Le TNFα a des effets complexes. Il peut activer de multiples voies de signalisation, parmi lesquelles l'induction de la synthèse de sphingolipides, et plus particulièrement de céramides, par la voie de novo et par l'activation des sphingomyélinases. Au niveau musculaire, les céramides sont connus pour leurs effets sur la signalisation de l'insuline, sur l'apoptose et sur la différenciation myogénique. Par contre, leur implication dans le cadre de l'atrophie n'avait jamais été prise en compte. L’objectif de ce travail a été dans un premier temps de démontrer le rôle des céramides dans l’atrophie. Dans un deuxième temps, nous avons caractérisé la voie de signalisation par laquelle l’augmentation intramusculaire de céramide induite par le TNFα aboutit à une chute de la synthèse protéique, couplée à une augmentation de la protéolyse. Dans ce but, nous avons mis au point des modèles in vitro d'atrophie, impliquant des myotubes traités par des concentrations physiologiques de TNF . Nous avons en parallèle étudié un modèle in vivo de cachexie induite chez la souris par l'implantation d’un adénocarcinome C26. L’analyse des sphingolipides nous a permis de montrer l’augmentation des taux de céramides concomitante à l’atrophie générée in vitro et in vivo. Le rôle des céramides dans l’atrophie a été démontré par l’effet protecteur des inhibiteurs de leur synthèse, dans les modèles in vitro et in vivo. Nous montrons de plus dans un modèle in vitro que les effets atrophiques des céramides sont dus à l’inhibition de la voie de signalisation Phospholipase D/mTOR/Akt. Nos résultats nous ont permis de prouver le rôle des sphingolipides dans le contrôle de l’homéostasie protéique du muscle. La modulation du métabolisme des sphingolipides apparaît donc comme une nouvelle cible thérapeutique prometteuse dans le traitement de la perte musculaire associée à diverses pathologies

Implication des céramides dans l'atrophie musculaire

Skeletal muscle demonstrated a remarkable plasticity in response to physiological changes, such as physical activity, and pathological situations. He suffered such severe atrophy during cachexia that accompanies various pathologies such as cancer, AIDS, etc.. Muscle atrophy is also a component of sarcopenia that occurs during normal aging, and is characterized by a decline in strength and muscle mass. Muscle atrophy, which leads to increased mortality and decreased treatment efficacy, thus constitutes a health problem majeur.La muscle wasting is characterized by an impaired balance between protein synthesis and degradation in adult fibers. Particularly high levels of circulating cytokines, including TNF, which affect muscle homeostasis via different signaling pathways appear to be the cause of atrophy. Mechanisms of muscle atrophy response to these elevated circulating levels are however unclear. TNFa has complex effects. It may activate multiple signaling pathways, including the induction of the synthesis of sphingolipids, especially ceramides, for the de novo pathway and the activation of sphingomyelinases. In muscle, ceramides are known for their effects on insulin signaling on apoptosis and myogenic differentiation. By cons, their involvement in the context of atrophy was never taken into account. The objective of this work was firstly to demonstrate the role of ceramides in atrophy. In a second step, we characterized the signaling pathway by which increased intramuscular ceramide induced by TNF leads to a fall in protein synthesis, coupled with an increase in proteolysis. For this purpose, we have developed in vitro models of atrophy involving myotubes treated with physiological concentrations of TNF . We studied in parallel an in vivo model of cachexia induced in mice by implantation of adenocarcinoma C26. Analysis of sphingolipids we showed increased levels of ceramide concomitant atrophy generated in vitro and in vivo. The role of ceramide in atrophy has been demonstrated by the protective effect of inhibitors of their synthesis in the in vitro and in vivo. We show further in an in vitro model that atrophic effects of ceramides are due to inhibition of phospholipase D signaling pathway / mTOR / Akt. Our results allowed us to prove the role of sphingolipids in the homeostatic control of muscle protein. Modulation of sphingolipid metabolism appears to be a promising new therapeutic target in the treatment of muscle wasting associated with various pathologies.Le muscle squelettique fait preuve d'une remarquable plasticité en réponse aux changements physiologiques, comme l’activité physique, et aux situations pathologiques. Il subit notamment une atrophie sévère lors de la cachexie qui accompagne diverses pathologies chroniques comme le cancer, le SIDA, etc. L’atrophie musculaire est aussi une composante de la sarcopénie qui survient lors du vieillissement normal, et se caractérise par un déclin de la force et de la masse musculaire. L'atrophie musculaire, qui entraîne une augmentation de la mortalité et diminue l’efficacité des traitements, constitue donc un problème de santé majeur.La fonte musculaire se caractérise par une altération de l’équilibre entre synthèse et dégradation protéiques dans les fibres adultes. Des taux particulièrement élevés de cytokines circulantes, dont le TNFα, qui affectent l’homéostasie du muscle via différentes voies de signalisation, semblent être à l’origine de l'atrophie. Les mécanismes de la réponse atrophique musculaire à ces taux circulants élevés sont cependant mal définis. Le TNFα a des effets complexes. Il peut activer de multiples voies de signalisation, parmi lesquelles l'induction de la synthèse de sphingolipides, et plus particulièrement de céramides, par la voie de novo et par l'activation des sphingomyélinases. Au niveau musculaire, les céramides sont connus pour leurs effets sur la signalisation de l'insuline, sur l'apoptose et sur la différenciation myogénique. Par contre, leur implication dans le cadre de l'atrophie n'avait jamais été prise en compte. L’objectif de ce travail a été dans un premier temps de démontrer le rôle des céramides dans l’atrophie. Dans un deuxième temps, nous avons caractérisé la voie de signalisation par laquelle l’augmentation intramusculaire de céramide induite par le TNFα aboutit à une chute de la synthèse protéique, couplée à une augmentation de la protéolyse. Dans ce but, nous avons mis au point des modèles in vitro d'atrophie, impliquant des myotubes traités par des concentrations physiologiques de TNF. Nous avons en parallèle étudié un modèle in vivo de cachexie induite chez la souris par l'implantation d’un adénocarcinome C26. L’analyse des sphingolipides nous a permis de montrer l’augmentation des taux de céramides concomitante à l’atrophie générée in vitro et in vivo. Le rôle des céramides dans l’atrophie a été démontré par l’effet protecteur des inhibiteurs de leur synthèse, dans les modèles in vitro et in vivo. Nous montrons de plus dans un modèle in vitro que les effets atrophiques des céramides sont dus à l’inhibition de la voie de signalisation Phospholipase D/mTOR/Akt. Nos résultats nous ont permis de prouver le rôle des sphingolipides dans le contrôle de l’homéostasie protéique du muscle. La modulation du métabolisme des sphingolipides apparaît donc comme une nouvelle cible thérapeutique prometteuse dans le traitement de la perte musculaire associée à diverses pathologies

Deciphering the Role of Schwann Cells in Inflammatory Peripheral Neuropathies Post Alphavirus Infection

Old world alphaviruses (e.g., chikungunya) are known to cause severe acute and chronic debilitating arthralgia/arthritis. However, atypical neurological manifestations and, in particular, unexpected cases of acute inflammatory Guillain–Barre syndrome (GBS) have been associated with the arthritogenic alphaviruses. The pathogenesis of alphavirus-associated GBS remains unclear. We herein addressed for the first time the role of Schwann cells (SC) in peripheral neuropathy post-alphaviral infection using the prototypical ONNV alphavirus model. We demonstrated that human SC expressed the recently identified alphavirus receptor MxRA8 and granting viral entry and robust replication. A canonical innate immune response was engaged by ONNV-infected SC with elevated gene expression for RIG-I, MDA5, IFN-β, and ISG15 and inflammatory chemokine CCL5. Transcription levels of prostaglandin E2-metabolizing enzymes including cPLA2α, COX-2, and mPGES-1 were also upregulated in ONNV-infected SC. Counterintuitively, we found that ONNV failed to affect SC regenerative properties as indicated by elevated expression of the pro-myelinating genes MPZ and MBP1 as well as the major pro-myelin transcription factor Egr2. While ONNV infection led to decreased expression of CD55 and CD59, essential to control complement bystander cytotoxicity, it increased TRAIL expression, a major pro-apoptotic T cell signal. Anti-apoptotic Bcl2 transcription levels were also increased in infected SC. Hence, our study provides new insights regarding the remarkable immunomodulatory role of SC of potential importance in the pathogenesis of GBS following alphavirus infection

Deciphering the Role of Schwann Cells in Inflammatory Peripheral Neuropathies Post Alphavirus Infection

Old world alphaviruses (e.g., chikungunya) are known to cause severe acute and chronic debilitating arthralgia/arthritis. However, atypical neurological manifestations and, in particular, unexpected cases of acute inflammatory Guillain–Barre syndrome (GBS) have been associated with the arthritogenic alphaviruses. The pathogenesis of alphavirus-associated GBS remains unclear. We herein addressed for the first time the role of Schwann cells (SC) in peripheral neuropathy post-alphaviral infection using the prototypical ONNV alphavirus model. We demonstrated that human SC expressed the recently identified alphavirus receptor MxRA8 and granting viral entry and robust replication. A canonical innate immune response was engaged by ONNV-infected SC with elevated gene expression for RIG-I, MDA5, IFN-β, and ISG15 and inflammatory chemokine CCL5. Transcription levels of prostaglandin E2-metabolizing enzymes including cPLA2α, COX-2, and mPGES-1 were also upregulated in ONNV-infected SC. Counterintuitively, we found that ONNV failed to affect SC regenerative properties as indicated by elevated expression of the pro-myelinating genes MPZ and MBP1 as well as the major pro-myelin transcription factor Egr2. While ONNV infection led to decreased expression of CD55 and CD59, essential to control complement bystander cytotoxicity, it increased TRAIL expression, a major pro-apoptotic T cell signal. Anti-apoptotic Bcl2 transcription levels were also increased in infected SC. Hence, our study provides new insights regarding the remarkable immunomodulatory role of SC of potential importance in the pathogenesis of GBS following alphavirus infection