PMID- 22257771
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20121002
LR  - 20211021
IS  - 2044-5040 (Electronic)
IS  - 2044-5040 (Linking)
VI  - 2
IP  - 1
DP  - 2012 Jan 18
TI  - TNF-alpha- and tumor-induced skeletal muscle atrophy involves sphingolipid 
      metabolism.
PG  - 2
LID - 10.1186/2044-5040-2-2 [doi]
AB  - 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-alpha, and in vivo in a murine model of 
      tumor-induced cachexia. Myotube atrophy induced by TNF-alpha 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-alpha, 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-alpha 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.
FAU - De Larichaudy, Joffrey
AU  - De Larichaudy J
AD  - Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut 
      National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
FAU - Zufferli, Alessandra
AU  - Zufferli A
AD  - Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut 
      National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
AD  - Istituto Interuniversitario di Miologia and Dipartimento di Istologia ed 
      Embriologia Medica, Universita di Roma-La Sapienza, 00161 Roma, Italy.
FAU - Serra, Filippo
AU  - Serra F
AD  - Istituto Interuniversitario di Miologia and Dipartimento di Istologia ed 
      Embriologia Medica, Universita di Roma-La Sapienza, 00161 Roma, Italy.
FAU - Isidori, Andrea M
AU  - Isidori AM
AD  - Dipartimento di Medicina Sperimentale, Universita di Roma-La Sapienza, 00161 
      Roma, Italy.
FAU - Naro, Fabio
AU  - Naro F
AD  - Istituto Interuniversitario di Miologia and Dipartimento di Istologia ed 
      Embriologia Medica, Universita di Roma-La Sapienza, 00161 Roma, Italy.
FAU - Dessalle, Kevin
AU  - Dessalle K
AD  - Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut 
      National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
FAU - Desgeorges, Marine
AU  - Desgeorges M
AD  - Lyon University, Laboratoire de Physiologie de l'Exercice EA 4338, University 
      Jean Monnet, F-42000 Saint Etienne, France.
FAU - Piraud, Monique
AU  - Piraud M
AD  - Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut 
      National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
AD  - Hospices Civils de Lyon, Service Maladies Hereditaires du Metabolisme et 
      Depistage Neonatal, F-69677 Bron, France.
FAU - Cheillan, David
AU  - Cheillan D
AD  - Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut 
      National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
AD  - Hospices Civils de Lyon, Service Maladies Hereditaires du Metabolisme et 
      Depistage Neonatal, F-69677 Bron, France.
FAU - Vidal, Hubert
AU  - Vidal H
AD  - Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut 
      National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
FAU - Lefai, Etienne
AU  - Lefai E
AD  - Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut 
      National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
FAU - Nemoz, Georges
AU  - Nemoz G
AD  - Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, Institut 
      National de la Recherche Agronomique UMR1235, INSA-Lyon, F-69600 Oullins, France.
LA  - eng
PT  - Journal Article
DEP - 20120118
PL  - England
TA  - Skelet Muscle
JT  - Skeletal muscle
JID - 101561193
PMC - PMC3344678
EDAT- 2012/01/20 06:00
MHDA- 2012/01/20 06:01
PMCR- 2012/01/18
CRDT- 2012/01/20 06:00
PHST- 2011/08/11 00:00 [received]
PHST- 2012/01/18 00:00 [accepted]
PHST- 2012/01/20 06:00 [entrez]
PHST- 2012/01/20 06:00 [pubmed]
PHST- 2012/01/20 06:01 [medline]
PHST- 2012/01/18 00:00 [pmc-release]
AID - 2044-5040-2-2 [pii]
AID - 10.1186/2044-5040-2-2 [doi]
PST - epublish
SO  - Skelet Muscle. 2012 Jan 18;2(1):2. doi: 10.1186/2044-5040-2-2.