| First Author | You JS | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 3 | Pages | 1551-63 |
| PubMed ID | 24302719 | Mgi Jnum | J:207172 |
| Mgi Id | MGI:5554625 | Doi | 10.1074/jbc.M113.531392 |
| Citation | You JS, et al. (2014) The role of diacylglycerol kinase zeta and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy. J Biol Chem 289(3):1551-63 |
| abstractText | The activation of mTOR signaling is essential for mechanically induced changes in skeletal muscle mass, and previous studies have suggested that mechanical stimuli activate mTOR (mammalian target of rapamycin) signaling through a phospholipase D (PLD)-dependent increase in the concentration of phosphatidic acid (PA). Consistent with this conclusion, we obtained evidence which further suggests that mechanical stimuli utilize PA as a direct upstream activator of mTOR signaling. Unexpectedly though, we found that the activation of PLD is not necessary for the mechanically induced increases in PA or mTOR signaling. Motivated by this observation, we performed experiments that were aimed at identifying the enzyme(s) that promotes the increase in PA. These experiments revealed that mechanical stimulation increases the concentration of diacylglycerol (DAG) and the activity of DAG kinases (DGKs) in membranous structures. Furthermore, using knock-out mice, we determined that the zeta isoform of DGK (DGKzeta) is necessary for the mechanically induced increase in PA. We also determined that DGKzeta significantly contributes to the mechanical activation of mTOR signaling, and this is likely driven by an enhanced binding of PA to mTOR. Last, we found that the overexpression of DGKzeta is sufficient to induce muscle fiber hypertrophy through an mTOR-dependent mechanism, and this event requires DGKzeta kinase activity (i.e. the synthesis of PA). Combined, these results indicate that DGKzeta, but not PLD, plays an important role in mechanically induced increases in PA and mTOR signaling. Furthermore, this study suggests that DGKzeta could be a fundamental component of the mechanism(s) through which mechanical stimuli regulate skeletal muscle mass. |
