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The regulation of skeletal muscle insulin‐stimulated signaling by the MEK‐REDD1‐mTOR axis
Author(s) -
Williamson David L,
Dungan Cory M
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.883.24
Subject(s) - mtorc1 , p70 s6 kinase 1 , endocrinology , medicine , pi3k/akt/mtor pathway , mapk/erk pathway , insulin receptor , insulin , phosphorylation , irs1 , kinase , protein kinase a , chemistry , protein kinase b , signal transduction , biology , microbiology and biotechnology , insulin resistance
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 10mg/kg BW of the MEK1/2 non‐competitive inhibitor, PD184352, 3 hours prior to acute insulin treatment (0.5 IU/kg BW). In separate studies, REDD1 KO mice were injected with 5mg/kg BW of the mTOR inhibitor, rapamycin, 3 hours prior to acute insulin treatment (0.5 IU/kg BW). 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 the 10 minute 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 mTORC1 signaling activation and reduced insulin stimulated IRS‐1 phosphorylation. Conversely, rapamycin inhibited S6K1 and rpS6 activation, and significantly improved IRS‐1 and MEK1/2 phosphorylation in KO mice. These data affirm 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. Support or Funding Information Mark Diamond Foundation