Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice
Abstract Background Although mounting evidence indicates that insulin resistance (IR) co‐occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-12-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
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| Online Access: | https://doi.org/10.1002/jcsm.12794 |
| _version_ | 1827279834315751424 |
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| author | Hyunjung Lee Tae Youl Ha Chang Hwa Jung Farida Sukma Nirmala So‐Young Park Yang Hoon Huh Jiyun Ahn |
| author_facet | Hyunjung Lee Tae Youl Ha Chang Hwa Jung Farida Sukma Nirmala So‐Young Park Yang Hoon Huh Jiyun Ahn |
| author_sort | Hyunjung Lee |
| collection | DOAJ |
| description | Abstract Background Although mounting evidence indicates that insulin resistance (IR) co‐occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was determined. Methods Six‐week‐old C57BL/6 mice were fed a high‐fat diet for 2 weeks to induce acute IR or for 24 weeks to induce chronic IR (n = 8 per group). To characterize mitochondrial function, we measured citrate synthase activity, ATP content, mitochondrial DNA (mtDNA) content, and oxygen consumption rate in gastrocnemius and liver tissues. We intraperitoneally administered mitochondrial division inhibitor 1 (mdivi‐1) to mice with acute IR and measured mitochondrial adaptive responses such as mitophagy, mitochondrial unfolded protein response (UPRmt), and oxidative stress (n = 6 per group). Results Acute IR occurred coincidently with impaired mitochondrial function, including reduced citrate synthase activity (−37.8%, P < 0.01), ATP production (−88.0%, P < 0.01), mtDNA (−53.1%, P < 0.01), and mitochondrial respiration (−52.2% for maximal respiration, P < 0.05) in skeletal muscle but not in liver. Administration of mdivi‐1 attenuated IR development by increasing mitochondrial function (+58.5% for mtDNA content, P < 0.01; 4.06 ± 0.69 to 5.84 ± 0.95 pmol/min/mg for citrate synthase activity, P < 0.05; 13.06 ± 0.70 to 34.87 ± 0.70 pmol/min/g for maximal respiration, P < 0.001). Western blot analysis showed acute IR resulted in increased autophagy (mitophagy) and UPRmt induction in muscle tissue. This adaptive response was inhibited by mdivi‐1, which reduced the mitochondrial oxidative stress of skeletal muscle during acute IR. Conclusions Acute IR induced mitochondrial oxidative stress that impaired mitochondrial function in skeletal muscle. Improving mitochondrial function has important potential for treating acute IR. |
| first_indexed | 2024-04-24T08:26:38Z |
| format | Article |
| id | doaj.art-2299ba47067b471886be78ee85e26845 |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2024-04-24T08:26:38Z |
| publishDate | 2021-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-2299ba47067b471886be78ee85e268452024-04-16T21:54:09ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092021-12-011261925193910.1002/jcsm.12794Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in miceHyunjung Lee0Tae Youl Ha1Chang Hwa Jung2Farida Sukma Nirmala3So‐Young Park4Yang Hoon Huh5Jiyun Ahn6Research Group of Natural Material and Metabolism Korea Food Research Institute Wanju Republic of KoreaResearch Group of Natural Material and Metabolism Korea Food Research Institute Wanju Republic of KoreaResearch Group of Natural Material and Metabolism Korea Food Research Institute Wanju Republic of KoreaResearch Group of Natural Material and Metabolism Korea Food Research Institute Wanju Republic of KoreaDepartment of Physiology, College of Medicine Yeungnam University Daegu Republic of KoreaCenter for Electron Microscopy Research Korea Basic Science Institute Cheongju Republic of KoreaResearch Group of Natural Material and Metabolism Korea Food Research Institute Wanju Republic of KoreaAbstract Background Although mounting evidence indicates that insulin resistance (IR) co‐occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was determined. Methods Six‐week‐old C57BL/6 mice were fed a high‐fat diet for 2 weeks to induce acute IR or for 24 weeks to induce chronic IR (n = 8 per group). To characterize mitochondrial function, we measured citrate synthase activity, ATP content, mitochondrial DNA (mtDNA) content, and oxygen consumption rate in gastrocnemius and liver tissues. We intraperitoneally administered mitochondrial division inhibitor 1 (mdivi‐1) to mice with acute IR and measured mitochondrial adaptive responses such as mitophagy, mitochondrial unfolded protein response (UPRmt), and oxidative stress (n = 6 per group). Results Acute IR occurred coincidently with impaired mitochondrial function, including reduced citrate synthase activity (−37.8%, P < 0.01), ATP production (−88.0%, P < 0.01), mtDNA (−53.1%, P < 0.01), and mitochondrial respiration (−52.2% for maximal respiration, P < 0.05) in skeletal muscle but not in liver. Administration of mdivi‐1 attenuated IR development by increasing mitochondrial function (+58.5% for mtDNA content, P < 0.01; 4.06 ± 0.69 to 5.84 ± 0.95 pmol/min/mg for citrate synthase activity, P < 0.05; 13.06 ± 0.70 to 34.87 ± 0.70 pmol/min/g for maximal respiration, P < 0.001). Western blot analysis showed acute IR resulted in increased autophagy (mitophagy) and UPRmt induction in muscle tissue. This adaptive response was inhibited by mdivi‐1, which reduced the mitochondrial oxidative stress of skeletal muscle during acute IR. Conclusions Acute IR induced mitochondrial oxidative stress that impaired mitochondrial function in skeletal muscle. Improving mitochondrial function has important potential for treating acute IR.https://doi.org/10.1002/jcsm.12794Insulin resistanceMitochondriaOxidative stressSkeletal muscleMitophagy |
| spellingShingle | Hyunjung Lee Tae Youl Ha Chang Hwa Jung Farida Sukma Nirmala So‐Young Park Yang Hoon Huh Jiyun Ahn Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice Journal of Cachexia, Sarcopenia and Muscle Insulin resistance Mitochondria Oxidative stress Skeletal muscle Mitophagy |
| title | Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice |
| title_full | Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice |
| title_fullStr | Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice |
| title_full_unstemmed | Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice |
| title_short | Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice |
| title_sort | mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice |
| topic | Insulin resistance Mitochondria Oxidative stress Skeletal muscle Mitophagy |
| url | https://doi.org/10.1002/jcsm.12794 |
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