Dungan Cory M, Gordon Bradley S, Williamson David L
Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, Lexington, Kentucky.
Department of Nutrition, Food, and Exercise Sciences, College of Human Sciences, Florida State University, Tallahassee, Florida.
Physiol Rep. 2019 Feb;7(4):e14011. doi: 10.14814/phy2.14011.
A loss of the regulated in development and DNA damage 1 (REDD1) hyperactivates mechanistic Target of Rapamycin Complex 1 (mTORC1) reducing insulin-stimulated insulin signaling, which could provide insight into mechanisms of insulin resistance. Although aerobic exercise acutely inhibits mTORC1 signaling, improvements in insulin-stimulated signaling are exhibited. The goal of this study was to determine if a single bout of treadmill exercise was sufficient to improve insulin signaling in mice lacking REDD1. REDD1 wildtype (WT) and REDD1 knockout (KO) mice were acutely exercised on a treadmill (30 min, 20 m/min, 5% grade). A within animal noninsulin-to-insulin-stimulated percent change in skeletal muscle insulin-stimulated kinases (IRS-1, ERK1/2, Akt), growth signaling activation (4E-BP1, S6K1), and markers of growth repression (REDD1, AMPK, FOXO1/3A) was examined, following no exercise control or an acute bout of exercise. Unlike REDD1 KO mice, REDD1 WT mice exhibited an increase (P < 0.05) in REDD1 following treadmill exercise. However, both REDD1 WT and KO mice exhibited an increase (P < 0.05) AMPK phosphorylation, and a subsequent reduction (P < 0.05) in mTORC1 signaling after the exercise bout versus nonexercising WT or KO mice. Exercise increased (P < 0.05) the noninsulin-to-insulin-stimulated percent change phosphorylation of mTORC1, ERK1/2, IRS-1, and Akt on S473 in REDD1 KO mice when compared to nonexercised KO mice. However, there was no change in the noninsulin-to-insulin-stimulated percent change activation of Akt on T308 and FOXO1/3A in the KO when compared to WT or KO mouse muscle after exercise. Our data show that a bout of treadmill exercise discriminately improves insulin-stimulated signaling in the absence of REDD1.
发育与DNA损伤调节因子1（REDD1）缺失会过度激活雷帕霉素机制性靶蛋白复合物1（mTORC1），从而降低胰岛素刺激的胰岛素信号传导，这可能有助于深入了解胰岛素抵抗的机制。尽管有氧运动可急性抑制mTORC1信号传导，但胰岛素刺激的信号传导仍会得到改善。本研究的目的是确定单次跑步机运动是否足以改善缺乏REDD1的小鼠的胰岛素信号传导。将REDD1野生型（WT）和REDD1基因敲除（KO）小鼠在跑步机上进行急性运动（30分钟，20米/分钟，5%坡度）。在无运动对照或急性运动后，检测动物体内骨骼肌胰岛素刺激激酶（IRS-1、ERK1/2、Akt）、生长信号激活（4E-BP1、S6K1）以及生长抑制标志物（REDD1、AMPK、FOXO1/3A）从非胰岛素刺激到胰岛素刺激的百分比变化。与REDD1基因敲除小鼠不同，REDD1野生型小鼠在跑步机运动后REDD1增加（P<0.05）。然而，与未运动的野生型或基因敲除小鼠相比，运动后REDD1野生型和基因敲除小鼠均表现出AMPK磷酸化增加（P<0.05），以及随后mTORC1信号传导减少（P<0.05）。与未运动的基因敲除小鼠相比，运动使REDD1基因敲除小鼠中mTORC1、ERK1/2、IRS-1和Akt在S473位点的非胰岛素刺激到胰岛素刺激的磷酸化百分比变化增加（P<0.05）。然而，与运动后的野生型或基因敲除小鼠肌肉相比，基因敲除小鼠中Akt在T308位点的激活以及FOXO1/3A从非胰岛素刺激到胰岛素刺激的百分比变化没有变化。我们的数据表明，单次跑步机运动在缺乏REDD1的情况下能特异性地改善胰岛素刺激的信号传导。
