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Theses

Implication des céramides dans l'atrophie musculaire

Abstract : 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.
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Submitted on : Friday, October 19, 2012 - 2:02:12 PM
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  • HAL Id : tel-00743546, version 1
  • PRODINRA : 329438

Citation

Joffrey De Larichaudy. Implication des céramides dans l'atrophie musculaire. Sciences agricoles. INSA de Lyon, 2012. Français. ⟨NNT : 2012ISAL0029⟩. ⟨tel-00743546⟩

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