The role of REDD1 in exercise-mediated insulin action
Dungan, Cory Michael
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REDD1 is a stress-activated protein that is upregulated during times of cell stress and nutrient deficiency, specifically, REDD1 inhibits mTORC1 activation to limit ATP consumption and promote cell survival. Recently, the importance of REDD1 has been linked to insulin signaling and metabolism, as a lack to REDD1 leads to reduced insulin-mediated IRS-1 activation. Fasted and fed studies from our lab using REDD1 wild type (WT) and REDD1 knockout (KO) mice suggest hyperactive mTORC1 limits the insulin stimulus from propagating down insulin signaling cascade in the absence of REDD1. The goal of the proposed studies was to 1) to address the role of REDD1 on insulin-stimulated signaling in skeletal muscle 2) to determine the potential mechanism behind the REDD1-mediated insulin signaling activation, and 3) to determine if an acute bout of aerobic exercise is sufficient to restore normal insulin signaling in REDD1 deficient mice. Using REDD1 WT and whole-body REDD1 KO mice, we measured markers of insulin signaling (IRS-1, Akt, MEK1/2, ERK1/2), mTORC1 inhibition (REDD1, AMPK), and growth signaling (S6K1, rpS6, 4E-BP1) before and after insulin stimulation (10 minutes). In our first study, we showed that a genetic, whole-body loss of REDD1 increased (p<0.05) mTORC1 and reduced (p<0.05) insulin-stimulated IRS-1 and Akt activation. In our second study, we showed for the first time in skeletal muscle that MEK inhibition reduced (p<0.05) REDD1 expression, which increased (p<0.05) mTORC1 and reduced (p<0.05) IRS-1 activation. When rapamycin was given to REDD1 KO mice, mTORC1 is reduced (p<0.05) and IRS-1 phosphorylation was increased (p<0.05). In our final study, an acute bout of aerobic exercise to increased (p<0.05) REDD1 expression in REDD1 WT mice, while it increased (p<0.05) AMPK, a potent mTORC1 inhibitor, in both REDD1 WT and REDD1 KO mice. There was a increase (p<0.05) in IRS-1 activation in both exercise groups, however the increase was greater (p<0.05) in the WT mice. Collectively, our data suggests that REDD1 is required for normal insulin-stimulated signaling, and a loss of REDD1 reduces IRS-1 activation because of hyperactive mTORC1 negative feedback. Additionally, reducing mTORC1 activation pharmacologically or with exercise increases IRS-1 activation, and improves insulin-stimulated signaling activation.