Phospholipase D regulates the size of skeletal muscle cells through the activation of mTOR signaling
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RESEARCH
Open Access
Phospholipase D regulates the size of skeletal muscle cells through the activation of mTOR signaling Rami Jaafar1, Joffrey De Larichaudy1, Stéphanie Chanon1, Vanessa Euthine1, Christine Durand1, Fabio Naro2, Philippe Bertolino3, Hubert Vidal1, Etienne Lefai1 and Georges Némoz1*
Abstract 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. Keywords: Phospholipase D, Phosphatidic acid, Muscle wasting, Muscle hypertrophy, Myotubes, mTOR
Lay abstract The phospholipase D (PLD) enzyme transforms phosphatidylcholine, a major lipid constituent of cell membranes, into a messenger endowed with many activities in the cell. PLD is known to influence the activity of mTOR, a signaling pathway that plays an important role in muscle mass regulation. We thus researched whether PLD had an effect on the size of cultured muscle cells. To this end, we used various types of PLD inhibitors, as well as systems allowing to modify PLD expression. We observed that both PLD inhibition and decreased expression induced muscle cell atrophy, associated with an increased expression of factors involved in protein * Correspondence: [email protected] 1 Lyon 1 University, INSERM U1060, CarMeN Laboratory, Institut National de la Recherche Agronomique USC1235, F-69600 Oullins, France Full list of author information is available at the end of the article
degradation. Conversely, overexpressing PLD induced a hypertrophy and a decreased expression of these factors. We further demonstrated that the changes
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