title: TNF-α- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism.
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.
authors.affiliation: Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
authors.forename: Joffrey
authors.initials: J
authors.lastname: De Larichaudy
authors.affiliation: Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.|Istituto Interuniversitario di Miologia and Dipartimento di Istologia ed Embriologia Medica, Università di Roma-La Sapienza, 00161 Roma, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zufferli
authors.affiliation: Istituto Interuniversitario di Miologia and Dipartimento di Istologia ed Embriologia Medica, Università di Roma-La Sapienza, 00161 Roma, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Serra
authors.affiliation: Dipartimento di Medicina Sperimentale, Università di Roma-La Sapienza, 00161 Roma, Italy.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Isidori
authors.affiliation: Istituto Interuniversitario di Miologia and Dipartimento di Istologia ed Embriologia Medica, Università di Roma-La Sapienza, 00161 Roma, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Naro
authors.affiliation: Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Dessalle
authors.affiliation: Lyon University, Laboratoire de Physiologie de l'Exercice EA 4338, University Jean Monnet, F-42000 Saint Etienne, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Desgeorges
authors.affiliation: Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.|Hospices Civils de Lyon, Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, F-69677 Bron, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Piraud
authors.affiliation: Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.|Hospices Civils de Lyon, Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, F-69677 Bron, France.
authors.forename: David
authors.initials: D
authors.lastname: Cheillan
authors.affiliation: Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.affiliation: Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.affiliation: Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Némoz