title: Phospholipase D regulates the size of skeletal muscle cells through the activation of mTOR signaling.
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.
authors.affiliation: Lyon 1 University, INSERM U1060, CarMeN Laboratory, Institut National de la Recherche Agronomique USC1235, F-69600 Oullins, France.
authors.forename: Rami
authors.initials: R
authors.lastname: Jaafar
authors.forename: Joffrey
authors.initials: J
authors.lastname: De Larichaudy
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Chanon
authors.forename: Vanessa
authors.initials: V
authors.lastname: Euthine
authors.forename: Christine
authors.initials: C
authors.lastname: Durand
authors.forename: Fabio
authors.initials: F
authors.lastname: Naro
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertolino
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.forename: Georges
authors.initials: G
authors.lastname: Némoz
mesh_terms: D000818:Animals; D048429:Cell Size; D003907:Dexamethasone; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology*; D009133:Muscular Atrophy / Q000139:chemically induced / Q000378:metabolism; D010712:Phosphatidic Acids / Q000494:pharmacology; D010739:Phospholipase D / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D046912:Multiprotein Complexes; D010712:Phosphatidic Acids; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D; C106801:phospholipase D1
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