Research

TNFalpha- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism

Joffrey De Larichaudy, Alessandra Zufferli, Filippo Serra, Andrea M Isidori, Fabio Naro, Kevin Dessalle, Marine Desgeorges, Monique Piraud, David Cheillan, Hubert Vidal, Etienne Lefai and Georges Nemoz

For all author emails, please log on.

Skeletal Muscle 2012, 2:2 doi:10.1186/2044-5040-2-2

Published: 18 January 2012

Abstract (provisional)

Background

Muscle atrophy associated with various pathophysiological conditions represents a major health problem, due to its contribution to the deterioration of patient status and its impact 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 by TNFalpha, and in vivo, in a murine model of tumor-induced cachexia. Myotube atrophy induced by TNFalpha 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 sphingomyelinases (GW4869 and 3-O-methylsphingomyelin). In the presence of TNFalpha, ceramide synthesis inhibitors significantly increased protein synthesis and decreased proteolysis. In parallel, they lowered the expression of both Atrogin-1 and LC3b genes, respectively involved in muscle protein degradation by proteasome, and autophagic proteolysis, 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 mTOR, and the mTOR substrates S6K1 and Akt. In vivo, C26 carcinoma implantation induced a substantial increase of muscle ceramide, together with drastic muscle atrophy. Treatment of the animals by myriocin reduced the expression of atrogenes Foxo3 and Atrogin-1, and partially protected muscle tissue from atrophy.

Conclusions

These results indicate that ceramide accumulation induced by TNFalpha or tumor development participates in the mechanism of muscle cell atrophy, and that sphingolipid metabolism can be a relevant target for pharmacological or nutritional interventions aiming at preserving muscle mass in pathological situations.