Regulation of skeletal muscle insulin-stimulated signaling through the MEK-REDD1-mTOR axis

Cory M. Dungan, David L. Williamson

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Recent findings in adipocytes suggest that mitogen-activated protein kinase (MAPK)/extracellular-regulated signaling kinase (ERK) kinase 1/2 (MEK1/2) signaling regulates regulated in development and DNA damage 1 (REDD1) protein expression. Similarly, our previous work show that a lack of REDD1 protein expression, and associated hyperactive basal mechanistic target of rapamycin (mTOR) signaling, limits skeletal muscle's response to insulin. Therefore, we sought to determine: 1) if MEK1/2 inhibition is sufficient to reduce REDD1 protein expression and subsequently insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation via negative feedback of hyperactive mTOR in REDD1 wild-type (WT) mice and 2) if rapamycin-mediated mTOR inhibition is sufficient to improve IRS-1 tyrosine phosphorylation in REDD1 knockout (KO) mice. REDD1 WT mice were injected with 10 mg/kg BW of the MEK1/2 non-competitive inhibitor, PD184352, 3 h prior to acute insulin treatment. In separate studies, REDD1 KO mice were injected with 5 mg/kg BW of the mTOR inhibitor, rapamycin, 3 h prior to acute insulin treatment. Following the inhibitor treatment period, markers of insulin signaling activation (IRS-1 Y1222, MEK1/2 S217/221, ERK1/2 T202/Y204), REDD1, and mTOR signaling activation (S6K1 T389, rpS6 S240/244) were examined in skeletal muscle collected before and after a 10 min insulin treatment. PD184352 treatment reduced MEK/ERK phosphorylation and REDD1 protein expression, independent of insulin. This reduction in REDD1 protein expression was associated with elevated basal S6K1 and rpS6 phosphorylation and reduced insulin stimulated IRS-1 phosphorylation. Conversely, rapamycin inhibited S6K1 and rpS6 activation, and significantly improved insulin –stimulated activation of IRS-1 and MEK1/2 in KO mice. These data support that REDD1 is required for normal insulin-stimulated signaling, and that a subtle balance exists between MEK1/2, REDD1, and mTOR for the proper regulation of insulin signaling.

Original languageEnglish (US)
Pages (from-to)1067-1072
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume482
Issue number4
DOIs
StatePublished - Jan 22 2017

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Regulation of skeletal muscle insulin-stimulated signaling through the MEK-REDD1-mTOR axis'. Together they form a unique fingerprint.

Cite this