Insulin resistance is not sustained following denervation in glycolytic skeletal muscle

Shawna L. McMillin, Erin C. Stanley, Luke A. Weyrauch, Jeffrey J. Brault, Barbara B. Kahn, Carol A. Witczak

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Denervation 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.

Original languageEnglish (US)
Article number4913
JournalInternational journal of molecular sciences
Volume22
Issue number9
DOIs
StatePublished - May 1 2021

Bibliographical note

Funding Information:
This research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases R01DK103562 (C.A.W.), R01DK043051 (B.B.K.); the National Institute of Arthritis and Musculoskeletal and Skin Diseases R01AR070200 (J.J.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, or the National Institutes of Health. The APC was funded by C.A.W.

Funding Information:
Funding: This research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases R01DK103562 (C.A.W.), R01DK043051 (B.B.K.); the National Institute of Arthritis and Musculoskeletal and Skin Diseases R01AR070200 (J.J.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, or the National Institutes of Health. The APC was funded by C.A.W.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Fiber type
  • Glucose transporter
  • Insulin signaling
  • Myosin heavy chain
  • Type 2 diabetes

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