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

doi:10.3390/ijms22094913

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

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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 language	English (US)
Article number	4913
Journal	International journal of molecular sciences
Volume	22
Issue number	9
DOIs	https://doi.org/10.3390/ijms22094913
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ijms22094913

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title = "Insulin resistance is not sustained following denervation in glycolytic skeletal muscle",

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.",

keywords = "Fiber type, Glucose transporter, Insulin signaling, Myosin heavy chain, Type 2 diabetes",

author = "McMillin, {Shawna L} and Stanley, {Erin C.} and Weyrauch, {Luke A.} and Brault, {Jeffrey J.} and Kahn, {Barbara B.} and Witczak, {Carol A.}",

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: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

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T1 - Insulin resistance is not sustained following denervation in glycolytic skeletal muscle

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AU - Stanley, Erin C.

AU - Weyrauch, Luke A.

AU - Brault, Jeffrey J.

AU - Kahn, Barbara B.

AU - Witczak, Carol A.

N1 - 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.

PY - 2021/5/1

Y1 - 2021/5/1

N2 - 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.

AB - 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.

KW - Fiber type

KW - Glucose transporter

KW - Insulin signaling

KW - Myosin heavy chain

KW - Type 2 diabetes

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Insulin resistance is not sustained following denervation in glycolytic skeletal muscle

Abstract

Bibliographical note

Keywords

UN SDGs

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