AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle Cells
Background: Activation of the unfolded protein response (UPR) is closely related to the pathogenesis of many metabolic disorders. Accumulating evidence also shows that UPR and metabolic signaling pathways are interdependent. The AMP-activated protein kinase (AMPK) signal pathway controls the energy...
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| Format: | Article |
| Language: | English |
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IMR Press
2023-08-01
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| Series: | Frontiers in Bioscience-Landmark |
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| Online Access: | https://www.imrpress.com/journal/FBL/28/8/10.31083/j.fbl2808159 |
| _version_ | 1797693182024089600 |
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| author | Jing Gong Lu Wang Wuchen Tao Xiangsheng Pang Zonghan Liu Shiming Li Wenjiong Li Xiaoping Chen Peng Zhang |
| author_facet | Jing Gong Lu Wang Wuchen Tao Xiangsheng Pang Zonghan Liu Shiming Li Wenjiong Li Xiaoping Chen Peng Zhang |
| author_sort | Jing Gong |
| collection | DOAJ |
| description | Background: Activation of the unfolded protein response (UPR) is closely related to the pathogenesis of many metabolic disorders. Accumulating evidence also shows that UPR and metabolic signaling pathways are interdependent. The AMP-activated protein kinase (AMPK) signal pathway controls the energy balance of eukaryotes. The aim of this study was therefore to investigate the possible interaction between AMPK signaling and UPR in muscle cells exposed to saturated fatty acids, as well as the potential mechanism. Methods: The saturated fatty acid palmitate was used to induce UPR in C2C12 myotubes. Compound C or knockdown of AMPKα with short hairpin RNA (shRNA) were used to inhibit the AMPK signaling pathway in palmitate-treated muscle cells. AMPK signaling in myotubes was activated using 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide (AICAR) or ex229. C2C12 myotubes were pre-treated with taurourdodeoxycholic acid (TUDCA) to inhibit UPR before adding palmitate. Real-time PCR and Western blotting were performed to evaluate the expression of UPR markers and activation of AMPK. Results: Palmitate treatment induced UPR in C2C12 myotubes while activating AMPK signaling. Inhibition of the AMPK pathway with compound C or AMPK shRNA reduced palmitate-induced activation of UPR, while inhibition of UPR with TUDCA reduced palmitate-induced AMPK activation. This indicates a positive feedback loop between UPR and AMPK. Furthermore, activation of the AMPK pathway with AICAR or ex229 caused a dose-dependent upregulation of UPR markers, including activating transcription factor 4 (ATF4), binding immunoglobulin protein (BIP), and growth arrest and DNA damage-inducible 34 (GADD34) protein. Conclusions: These results provide the first evidence that AMPK signaling is involved in the early activation of UPR caused by saturated fatty acids in skeletal muscle. Furthermore, they indicate that physiological or pharmacological activation of the AMPK pathway (e.g., by exercise or phenformin, respectively) can promote muscle health and function, thereby improving the quality of life in individuals with metabolic disorders due to a high-fat diet or obesity. |
| first_indexed | 2024-03-12T02:39:51Z |
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| institution | Directory Open Access Journal |
| issn | 2768-6701 |
| language | English |
| last_indexed | 2024-03-12T02:39:51Z |
| publishDate | 2023-08-01 |
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| spelling | doaj.art-fd591b8f350d4976a01db4fde1bed19c2023-09-04T09:13:41ZengIMR PressFrontiers in Bioscience-Landmark2768-67012023-08-0128815910.31083/j.fbl2808159S2768-6701(23)00804-3AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle CellsJing Gong0Lu Wang1Wuchen Tao2Xiangsheng Pang3Zonghan Liu4Shiming Li5Wenjiong Li6Xiaoping Chen7Peng Zhang8State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, ChinaState Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, ChinaState Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, ChinaState Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, ChinaState Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, ChinaState Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, ChinaState Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, ChinaState Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, ChinaState Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, ChinaBackground: Activation of the unfolded protein response (UPR) is closely related to the pathogenesis of many metabolic disorders. Accumulating evidence also shows that UPR and metabolic signaling pathways are interdependent. The AMP-activated protein kinase (AMPK) signal pathway controls the energy balance of eukaryotes. The aim of this study was therefore to investigate the possible interaction between AMPK signaling and UPR in muscle cells exposed to saturated fatty acids, as well as the potential mechanism. Methods: The saturated fatty acid palmitate was used to induce UPR in C2C12 myotubes. Compound C or knockdown of AMPKα with short hairpin RNA (shRNA) were used to inhibit the AMPK signaling pathway in palmitate-treated muscle cells. AMPK signaling in myotubes was activated using 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide (AICAR) or ex229. C2C12 myotubes were pre-treated with taurourdodeoxycholic acid (TUDCA) to inhibit UPR before adding palmitate. Real-time PCR and Western blotting were performed to evaluate the expression of UPR markers and activation of AMPK. Results: Palmitate treatment induced UPR in C2C12 myotubes while activating AMPK signaling. Inhibition of the AMPK pathway with compound C or AMPK shRNA reduced palmitate-induced activation of UPR, while inhibition of UPR with TUDCA reduced palmitate-induced AMPK activation. This indicates a positive feedback loop between UPR and AMPK. Furthermore, activation of the AMPK pathway with AICAR or ex229 caused a dose-dependent upregulation of UPR markers, including activating transcription factor 4 (ATF4), binding immunoglobulin protein (BIP), and growth arrest and DNA damage-inducible 34 (GADD34) protein. Conclusions: These results provide the first evidence that AMPK signaling is involved in the early activation of UPR caused by saturated fatty acids in skeletal muscle. Furthermore, they indicate that physiological or pharmacological activation of the AMPK pathway (e.g., by exercise or phenformin, respectively) can promote muscle health and function, thereby improving the quality of life in individuals with metabolic disorders due to a high-fat diet or obesity.https://www.imrpress.com/journal/FBL/28/8/10.31083/j.fbl2808159palmitateer stressunfolded protein responseampkc2c12 myotube |
| spellingShingle | Jing Gong Lu Wang Wuchen Tao Xiangsheng Pang Zonghan Liu Shiming Li Wenjiong Li Xiaoping Chen Peng Zhang AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle Cells Frontiers in Bioscience-Landmark palmitate er stress unfolded protein response ampk c2c12 myotube |
| title | AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle Cells |
| title_full | AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle Cells |
| title_fullStr | AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle Cells |
| title_full_unstemmed | AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle Cells |
| title_short | AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle Cells |
| title_sort | ampk mediates early activation of the unfolded protein response through a positive feedback loop in palmitate treated muscle cells |
| topic | palmitate er stress unfolded protein response ampk c2c12 myotube |
| url | https://www.imrpress.com/journal/FBL/28/8/10.31083/j.fbl2808159 |
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