Skip to main content

The role of diacylglycerol kinase ζ and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy.

Publication ,  Journal Article
You, J-S; Lincoln, HC; Kim, C-R; Frey, JW; Goodman, CA; Zhong, X-P; Hornberger, TA
Published in: J Biol Chem
January 17, 2014

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 ζ isoform of DGK (DGKζ) is necessary for the mechanically induced increase in PA. We also determined that DGKζ 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 DGKζ is sufficient to induce muscle fiber hypertrophy through an mTOR-dependent mechanism, and this event requires DGKζ kinase activity (i.e. the synthesis of PA). Combined, these results indicate that DGKζ, but not PLD, plays an important role in mechanically induced increases in PA and mTOR signaling. Furthermore, this study suggests that DGKζ could be a fundamental component of the mechanism(s) through which mechanical stimuli regulate skeletal muscle mass.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

January 17, 2014

Volume

289

Issue

3

Start / End Page

1551 / 1563

Location

United States

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Phosphatidic Acids
  • Organ Size
  • Muscle, Skeletal
  • Muscle Proteins
  • Mice, Knockout
  • Mice
  • Isoenzymes
  • Hypertrophy
 

Citation

APA
Chicago
ICMJE
MLA
NLM
You, J.-S., Lincoln, H. C., Kim, C.-R., Frey, J. W., Goodman, C. A., Zhong, X.-P., & Hornberger, T. A. (2014). The role of diacylglycerol kinase ζ and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy. J Biol Chem, 289(3), 1551–1563. https://doi.org/10.1074/jbc.M113.531392
You, Jae-Sung, Hannah C. Lincoln, Chan-Ran Kim, John W. Frey, Craig A. Goodman, Xiao-Ping Zhong, and Troy A. Hornberger. “The role of diacylglycerol kinase ζ and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy.J Biol Chem 289, no. 3 (January 17, 2014): 1551–63. https://doi.org/10.1074/jbc.M113.531392.
You, Jae-Sung, et al. “The role of diacylglycerol kinase ζ and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy.J Biol Chem, vol. 289, no. 3, Jan. 2014, pp. 1551–63. Pubmed, doi:10.1074/jbc.M113.531392.
You J-S, Lincoln HC, Kim C-R, Frey JW, Goodman CA, Zhong X-P, Hornberger TA. The role of diacylglycerol kinase ζ and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy. J Biol Chem. 2014 Jan 17;289(3):1551–1563.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

January 17, 2014

Volume

289

Issue

3

Start / End Page

1551 / 1563

Location

United States

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Phosphatidic Acids
  • Organ Size
  • Muscle, Skeletal
  • Muscle Proteins
  • Mice, Knockout
  • Mice
  • Isoenzymes
  • Hypertrophy