A role for REDD1 on insulin‐stimulated signaling activation following acute treadmill exercise

Abstract

The protein, regulated in development and DNA damage 1 (REDD1), has been suggested to be a required molecule for normal insulin‐stimulated signaling, as a loss of REDD1 reduces insulin signaling, potentially through hyperactive mechanistic target of rapamycin (mTOR) signaling. Aerobic exercise inhibits mTORC1 activation and improves insulin signaling protein responses to insulin. Thus, the goal of this study was to determine if an acute bout of aerobic exercise was sufficient to improve insulin signaling in mice lacking REDD1. REDD1 wildtype (WT) and REDD1 knockout (KO) mice underwent an acute bout of treadmill exercise for 30 minutes at 20m/min on a 5% grade or remained sedentary. The plantar flexor complex group was then removed from the lower limbs before or after receiving acute insulin treatment (0.5 IU/kg BW) Changes to skeletal muscle insulin (IRS‐1 Y1222, Akt S473) and mTOR (4E‐BP1 S37/46, S6K1 T389) signaling intermediates, along with markers of acute aerobic exercise (REDD1, AMPK T172, ERK1/2 T202/Y204), were determined immediately after the exercise bout, before and after IP insulin treatment (10 min). Despite no effect of insulin, aerobic exercise significantly increased (p<0.05) REDD1 expression in the WT mice versus sedentary mice. As expected, there was no observable REDD1 protein expression in the KO mice. AMPK activation was significantly elevated (p<0.05) following the acute bout of exercise in both WT and KO versus sedentary mice, though no effect of insulin was observed. Conversely, a significantly greater reduction (p<0.05) in 4E‐BP1 and S6K1 activation was observed in the exercised KO mice versus the exercised WT mice, which then contributed to significantly greater responses (p<0.05 versus exercise+insulin WT mice) to insulin by the exercised KO mice. Lastly, a significantly greater activation (p<0.05) of IRS‐1 and ERK1/2 was observed in response to insulin in the exercise+insulin KO mice versus exercise+insulin WT mice. Our data show that an acute bout of aerobic exercise is sufficient to improve insulin‐stimulated signaling in the absence of REDD1, but REDD1 is still required for a normal insulin signaling response independent of exercise.Support or Funding InformationMark Diamond Foundation