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Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation
Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529411/ https://www.ncbi.nlm.nih.gov/pubmed/28747716 http://dx.doi.org/10.1038/s41598-017-07011-3 |
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author | Nakazawa, Harumasa Ikeda, Kazuhiro Shinozaki, Shohei Kobayashi, Masayuki Ikegami, Yuichi Fu, Ming Nakamura, Tomoyuki Yasuhara, Shingo Yu, Yong-Ming Martyn, J. A. Jeevendra Tompkins, Ronald G. Shimokado, Kentaro Yorozu, Tomoko Ito, Hideki Inoue, Satoshi Kaneki, Masao |
author_facet | Nakazawa, Harumasa Ikeda, Kazuhiro Shinozaki, Shohei Kobayashi, Masayuki Ikegami, Yuichi Fu, Ming Nakamura, Tomoyuki Yasuhara, Shingo Yu, Yong-Ming Martyn, J. A. Jeevendra Tompkins, Ronald G. Shimokado, Kentaro Yorozu, Tomoko Ito, Hideki Inoue, Satoshi Kaneki, Masao |
author_sort | Nakazawa, Harumasa |
collection | PubMed |
description | Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients. |
format | Online Article Text |
id | pubmed-5529411 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-55294112017-08-02 Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation Nakazawa, Harumasa Ikeda, Kazuhiro Shinozaki, Shohei Kobayashi, Masayuki Ikegami, Yuichi Fu, Ming Nakamura, Tomoyuki Yasuhara, Shingo Yu, Yong-Ming Martyn, J. A. Jeevendra Tompkins, Ronald G. Shimokado, Kentaro Yorozu, Tomoko Ito, Hideki Inoue, Satoshi Kaneki, Masao Sci Rep Article Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients. Nature Publishing Group UK 2017-07-26 /pmc/articles/PMC5529411/ /pubmed/28747716 http://dx.doi.org/10.1038/s41598-017-07011-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Nakazawa, Harumasa Ikeda, Kazuhiro Shinozaki, Shohei Kobayashi, Masayuki Ikegami, Yuichi Fu, Ming Nakamura, Tomoyuki Yasuhara, Shingo Yu, Yong-Ming Martyn, J. A. Jeevendra Tompkins, Ronald G. Shimokado, Kentaro Yorozu, Tomoko Ito, Hideki Inoue, Satoshi Kaneki, Masao Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation |
title | Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation |
title_full | Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation |
title_fullStr | Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation |
title_full_unstemmed | Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation |
title_short | Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation |
title_sort | burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of hif-1α and mtorc1: role of protein farnesylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529411/ https://www.ncbi.nlm.nih.gov/pubmed/28747716 http://dx.doi.org/10.1038/s41598-017-07011-3 |
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