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Lina M. Obeid - One of the best experts on this subject based on the ideXlab platform.

  • Probing de novo Sphingolipid Metabolism in mammalian cells utilizing mass spectrometry.
    Journal of lipid research, 2018
    Co-Authors: Justin Snider, Lina M. Obeid, Chiara Luberto, Ashley J. Snider, Yusuf A. Hannun
    Abstract:

    Sphingolipids constitute a dynamic metabolic network that interconnects several bioactive molecules, including ceramide (Cer), sphingosine (Sph), Sph 1-phosphate, and Cer 1-phosphate. The interconversion of these metabolites is controlled by a cohort of at least 40 enzymes, many of which respond to endogenous or exogenous stimuli. Typical probing of the Sphingolipid pathway relies on Sphingolipid mass levels or determination of the activity of individual enzymes. Either approach is unable to provide a complete analysis of flux through Sphingolipid Metabolism, which, given the interconnectivity of the Sphingolipid pathway, is critical information to identify nodes of regulation. Here, we present a one-step in situ assay that comprehensively probes the flux through de novo Sphingolipid synthesis, post serine palmitoyltransferase, by monitoring the incorporation and Metabolism of the 17 carbon dihydrosphingosine precursor with LC/MS. Pulse labeling and analysis of precursor Metabolism identified sequential well-defined phases of Sphingolipid synthesis, corresponding to the activity of different enzymes in the pathway, further confirmed by the use of specific inhibitors and modulators of Sphingolipid Metabolism. This work establishes precursor pulse labeling as a practical tool for comprehensively studying metabolic flux through de novo Sphingolipid synthesis and complex Sphingolipid generation.

  • evolving concepts in cancer therapy through targeting Sphingolipid Metabolism
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Jeanphilip Truman, Lina M. Obeid, Monica Garciabarros, Yusuf A. Hannun
    Abstract:

    Traditional methods of cancer treatment are limited in their efficacy due to both inherent and acquired factors. Many different studies have shown that the generation of ceramide in response to cytotoxic therapy is generally an important step leading to cell death. Cancer cells employ different methods to both limit ceramide generation and to remove ceramide in order to become resistant to treatment. Furthermore, sphingosine kinase activity, which phosphorylates sphingosine the product of ceramide hydrolysis, has been linked to multidrug resistance, and can act as a strong survival factor. This review will examine several of the most frequently used cancer therapies and their effect on both ceramide generation and the mechanisms employed to remove it. The development and use of inhibitors of sphingosine kinase will be focused upon as an example of how targeting Sphingolipid Metabolism may provide an effective means to improve treatment response rates and reduce associated treatment toxicity. This article is part of a Special Issue entitled Tools to study lipid functions.

  • Sphingolipid Metabolism cooperates with bak and bax to promote the mitochondrial pathway of apoptosis
    Cell, 2012
    Co-Authors: Jerry E Chipuk, Lina M. Obeid, Gavin P Mcstay, Archana Bharti, Tomomi Kuwana, Christopher J Clarke, Leah J Siskind, Douglas R Green
    Abstract:

    Summary Mitochondria are functionally and physically associated with heterotypic membranes, yet little is known about how these interactions impact mitochondrial outer-membrane permeabilization (MOMP) and apoptosis. We observed that dissociation of heterotypic membranes from mitochondria inhibited BAK/BAX-dependent cytochrome c (cyto c ) release. Biochemical purification of neutral sphingomyelinases that correlated with MOMP sensitization suggested that Sphingolipid Metabolism coordinates BAK/BAX activation. Using purified lipids and enzymes, sensitivity to MOMP was achieved by in vitro reconstitution of the Sphingolipid metabolic pathway. Sphingolipid Metabolism inhibitors blocked MOMP from heavy membrane preparations but failed to influence MOMP in the presence of Sphingolipid-reconstituted, purified mitochondria. Furthermore, the Sphingolipid products, sphingosine-1-PO 4 and hexadecenal, cooperated specifically with BAK and BAX, respectively. Sphingolipid Metabolism was also required for cellular responses to apoptosis. Our studies suggest that BAK/BAX activation and apoptosis are coordinated through BH3-only proteins and a specific lipid milieu that is maintained by heterotypic membrane-mitochondrial interactions.

  • ceramide synthases at the centre of Sphingolipid Metabolism and biology
    Biochemical Journal, 2012
    Co-Authors: Thomas D Mulle, Yusuf A Hannu, Lina M. Obeid
    Abstract:

    Sphingolipid Metabolism in metazoan cells consists of a complex interconnected web of numerous enzymes, metabolites and modes of regulation. At the centre of Sphingolipid Metabolism reside CerSs (ceramide synthases), a group of enzymes that catalyse the formation of ceramides from sphingoid base and acyl-CoA substrates. From a metabolic perspective, these enzymes occupy a unique niche in that they simultaneously regulate de novo Sphingolipid synthesis and the recycling of free sphingosine produced from the degradation of pre-formed Sphingolipids (salvage pathway). Six mammalian CerSs (CerS1–CerS6) have been identified. Unique characteristics have been described for each of these enzymes, but perhaps the most notable is the ability of individual CerS isoforms to produce ceramides with characteristic acyl-chain distributions. Through this control of acyl-chain length and perhaps in a compartment-specific manner, CerSs appear to regulate multiple aspects of Sphingolipid-mediated cell and organismal biology. In the present review, we discuss the function of CerSs as critical regulators of Sphingolipid Metabolism, highlight their unique characteristics and explore the emerging roles of CerSs in regulating programmed cell death, cancer and many other aspects of biology.

  • Yeast Sphingolipid Metabolism: clues and connections.
    Biochemistry and cell biology = Biochimie et biologie cellulaire, 2004
    Co-Authors: Kellie J. Sims, Stefka D. Spassieva, Eberhard O. Voit, Lina M. Obeid
    Abstract:

    This review of Sphingolipid Metabolism in the budding yeast Saccharomyces cerevisiae contains information on the enzymes and the genes that encode them, as well as connections to other metabolic pa...

Joffrey De Larichaudy - One of the best experts on this subject based on the ideXlab platform.

  • tnf α and tumor induced skeletal muscle atrophy involves Sphingolipid Metabolism
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan
    Abstract:

    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. 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. 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.

  • TNF-α- and tumor-induced skeletal muscle atrophy involves Sphingolipid Metabolism
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan, Hubert Vidal
    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.

  • TNF-α- and tumor-induced skeletal muscle atrophy involves Sphingolipid Metabolism.
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan, Hubert Vidal
    Abstract:

    UNLABELLED: 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.

Hubert Vidal - One of the best experts on this subject based on the ideXlab platform.

  • TNF-α- and tumor-induced skeletal muscle atrophy involves Sphingolipid Metabolism
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan, Hubert Vidal
    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.

  • TNF-α- and tumor-induced skeletal muscle atrophy involves Sphingolipid Metabolism.
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan, Hubert Vidal
    Abstract:

    UNLABELLED: 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.

David Cheillan - One of the best experts on this subject based on the ideXlab platform.

  • tnf α and tumor induced skeletal muscle atrophy involves Sphingolipid Metabolism
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan
    Abstract:

    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. 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. 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.

  • TNF-α- and tumor-induced skeletal muscle atrophy involves Sphingolipid Metabolism
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan, Hubert Vidal
    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.

  • TNF-α- and tumor-induced skeletal muscle atrophy involves Sphingolipid Metabolism.
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan, Hubert Vidal
    Abstract:

    UNLABELLED: 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.

Alessandra Zufferli - One of the best experts on this subject based on the ideXlab platform.

  • tnf α and tumor induced skeletal muscle atrophy involves Sphingolipid Metabolism
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan
    Abstract:

    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. 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. 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.

  • TNF-α- and tumor-induced skeletal muscle atrophy involves Sphingolipid Metabolism
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan, Hubert Vidal
    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.

  • TNF-α- and tumor-induced skeletal muscle atrophy involves Sphingolipid Metabolism.
    Skeletal Muscle, 2012
    Co-Authors: Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan, Hubert Vidal
    Abstract:

    UNLABELLED: 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.