Acute treadmill exercise discriminately improves the skeletal muscle insulin-stimulated growth signaling responses in mice lacking REDD1.

Bradley S Gordon,David L Williamson,Cory M Dungan

doi:10.14814/phy2.14011

Abstract

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.

Highlights

25 million Americans are diagnosed with diabetes (American Diabetes A, 2018) which impacts the normal physiologic response to insulin-stimulated glucose uptake (Hansen et al 1995; Wang et al 1999), lipid storage (Porstmann et al 2008), protein synthesis (Vander Haar et al 2007), and cell growth and survival (Brunet et al 1999) among other functions
We previously reported that a lack of regulated in development and DNA damage 1 (REDD1) reduces glucose tolerance and insulin-stimulated signaling in skeletal muscle, which was associated with hyperactive mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling and potential negative feedback on insulin receptor substrate-1 (IRS-1) (Wilkinson et al 2012; Dungan et al 2014; Williamson et al 2014)
Consistent with our previous work (Dungan et al 2014; Williamson et al 2014; Dungan and Williamson 2017), REDD1 protein expression was not detectable in REDD1 KO mouse skeletal muscle during either a basal/fasted state, after an acute bout of treadmill exercise, or after insulin treatment when compared to REDD1 WT mouse muscle (Fig. 2B)

Summary

Introduction

25 million Americans are diagnosed with diabetes (American Diabetes A, 2018) which impacts the normal physiologic response to insulin-stimulated glucose uptake (Hansen et al 1995; Wang et al 1999), lipid storage (Porstmann et al 2008), protein synthesis (Vander Haar et al 2007), and cell growth and survival (Brunet et al 1999) among other functions. IRS-1 can stimulate downstream signaling kinases, including protein kinase B/ Akt (Vanhaesebroeck and Alessi 2000) and the mitogenactivated protein kinase (MAPK) pathways to promote cell metabolism, growth, and proliferation (Weng et al 2001). Akt activation indirectly promotes the activation of mechanistic target of rapamycin complex I (mTORC1) (Vander Haar et al 2007) by phosphorylating the tuberous sclerosis complex 2 (TSC2) protein, inhibiting the TSC1/2 complex (Potter et al 2002).

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