Phospholipase D regulates the size of skeletal muscle cells through the activation of mTOR signaling

Cell Communication and Signaling

Research

Philippe Bertolino¹  Stéphanie Chanon²  Etienne Lefai²  Christine Durand²  Georges Némoz²  Rami Jaafar²  Vanessa Euthine²  Hubert Vidal²  Joffrey De Larichaudy²  Fabio Naro³ 

[1] Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, 69008, Lyon, France;INSERM U1060, CarMeN Laboratory, Institut National de la Recherche Agronomique USC1235, Lyon 1 University, F-69600, Oullins, France;Istituto Interuniversitario di Miologia and Dipartimento di Istologia ed Embriologia Medica, Università di Roma-La Sapienza, 00161, Roma, Italy;

关键词: Phospholipase D;    Phosphatidic acid;    Muscle wasting;    Muscle hypertrophy;    Myotubes;    mTOR;   

DOI  :  10.1186/1478-811X-11-55

 received in 2012-11-27, accepted in 2013-07-18,  发布年份 2013

来源: Springer

【 摘 要 】

mTOR is a major actor of skeletal muscle mass regulation in situations of atrophy or hypertrophy. It is established that Phospholipase D (PLD) activates mTOR signaling, through the binding of its product phosphatidic acid (PA) to mTOR protein. An influence of PLD on muscle cell size could thus be suspected. We explored the consequences of altered expression and activity of PLD isoforms in differentiated L6 myotubes. Inhibition or down-regulation of the PLD1 isoform markedly decreased myotube size and muscle specific protein content. Conversely, PLD1 overexpression induced muscle cell hypertrophy, both in vitro in myotubes and in vivo in mouse gastrocnemius. In the presence of atrophy-promoting dexamethasone, PLD1 overexpression or addition of exogenous PA protected myotubes against atrophy. Similarly, exogenous PA protected myotubes against TNFα-induced atrophy. Moreover, the modulation of PLD expression or activity in myotubes showed that PLD1 negatively regulates the expression of factors involved in muscle protein degradation, such as the E3-ubiquitin ligases Murf1 and Atrogin-1, and the Foxo3 transcription factor. Inhibition of mTOR by PP242 abolished the positive effects of PLD1 on myotubes, whereas modulating PLD influenced the phosphorylation of both S6K1 and Akt, which are respectively substrates of mTORC1 and mTORC2 complexes. These observations suggest that PLD1 acts through the activation of both mTORC1 and mTORC2 to induce positive trophic effects on muscle cells. This pathway may offer interesting therapeutic potentialities in the treatment of muscle wasting.

【 授权许可】

Unknown   
© Jaafar et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.