The role of striated muscle Pik3r1 in glucose and protein metabolism following chronic glucocorticoid exposure
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved..
Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remain unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone (DEX), a synthetic glucocorticoid. Treating wildtype (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue, and gastrocnemius (GA) muscle. This DEX effect was diminished in GA muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in GA muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced GA myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice, and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:296 |
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| Enthalten in: |
The Journal of biological chemistry - 296(2021) vom: 30. Jan., Seite 100395 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Tzu-Chieh [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.09.2021 Date Revised 09.09.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2021.100395 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Chen, Tzu-Chieh |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The role of striated muscle Pik3r1 in glucose and protein metabolism following chronic glucocorticoid exposure |
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| 500 | |a Date Completed 09.09.2021 | ||
| 500 | |a Date Revised 09.09.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remain unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone (DEX), a synthetic glucocorticoid. Treating wildtype (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue, and gastrocnemius (GA) muscle. This DEX effect was diminished in GA muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in GA muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced GA myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice, and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Pik3r1 | |
| 650 | 4 | |a glucocorticoid receptor | |
| 650 | 4 | |a glucocorticoids | |
| 650 | 4 | |a insulin resistance | |
| 650 | 4 | |a protein synthesis | |
| 650 | 4 | |a skeletal muscle | |
| 650 | 4 | |a striated muscle | |
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| 650 | 7 | |a Insulin |2 NLM | |
| 650 | 7 | |a Class Ia Phosphatidylinositol 3-Kinase |2 NLM | |
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| 650 | 7 | |a EC 2.7.1.137 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Glucose |2 NLM | |
| 650 | 7 | |a IY9XDZ35W2 |2 NLM | |
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| 700 | 1 | |a Dandan, Mohamad |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Rebecca A |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Maggie |e verfasserin |4 aut | |
| 700 | 1 | |a Villivalam, Sneha D |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Szu-Chi |e verfasserin |4 aut | |
| 700 | 1 | |a Costello, Damian |e verfasserin |4 aut | |
| 700 | 1 | |a Shankaran, Mahalakshmi |e verfasserin |4 aut | |
| 700 | 1 | |a Mohammed, Hussein |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Sona |e verfasserin |4 aut | |
| 700 | 1 | |a Hellerstein, Marc K |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jen-Chywan |e verfasserin |4 aut | |
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