McMillin, Shawna L.Stanley, Erin C.Weyrauch, Luke A.Brault, Jeffrey J.Kahn, Barbara B.Witczak, Carol A.2022-09-212022-09-212021-05-06McMillin SL, Stanley EC, Weyrauch LA, Brault JJ, Kahn BB, Witczak CA. Insulin Resistance Is Not Sustained Following Denervation in Glycolytic Skeletal Muscle. Int J Mol Sci. 2021;22(9):4913. Published 2021 May 6. doi:10.3390/ijms22094913https://hdl.handle.net/1805/30085Denervation rapidly induces insulin resistance (i.e., impairments in insulin-stimulated glucose uptake and signaling proteins) in skeletal muscle. Surprisingly, whether this metabolic derangement is long-lasting is presently not clear. The main goal of this study was to determine if insulin resistance is sustained in both oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles following long-term (28 days) denervation. Mouse hindlimb muscles were denervated via unilateral sciatic nerve resection. Both soleus and EDL muscles atrophied ~40%. Strikingly, while denervation impaired submaximal insulin-stimulated [3H]-2-deoxyglucose uptake ~30% in the soleus, it enhanced submaximal (~120%) and maximal (~160%) insulin-stimulated glucose uptake in the EDL. To assess possible mechanism(s), immunoblots were performed. Denervation did not consistently alter insulin signaling (e.g., p-Akt (Thr308):Akt; p-TBC1D1 [phospho-Akt substrate (PAS)]:TBC1D1; or p-TBC1D4 (PAS):TBC1D4) in either muscle. However, denervation decreased glucose transporter 4 (GLUT4) levels ~65% in the soleus but increased them ~90% in the EDL. To assess the contribution of GLUT4 to the enhanced EDL muscle glucose uptake, muscle-specific GLUT4 knockout mice were examined. Loss of GLUT4 prevented the denervation-induced increase in insulin-stimulated glucose uptake. In conclusion, the denervation results sustained insulin resistance in the soleus but enhanced insulin sensitivity in the EDL due to increased GLUT4 protein levels.en-USAttribution 4.0 InternationalFiber typeGlucose transporterInsulin signalingMyosin heavy chainType 2 diabetesArticle