Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation

Abstract 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...

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Autores principales:	Harumasa Nakazawa, Kazuhiro Ikeda, Shohei Shinozaki, Masayuki Kobayashi, Yuichi Ikegami, Ming Fu, Tomoyuki Nakamura, Shingo Yasuhara, Yong-Ming Yu, J. A. Jeevendra Martyn, Ronald G. Tompkins, Kentaro Shimokado, Tomoko Yorozu, Hideki Ito, Satoshi Inoue, Masao Kaneki
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/afe79a61568341ec8376c8fb9c5a6d31
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spelling	oai:doaj.org-article:afe79a61568341ec8376c8fb9c5a6d312021-12-02T16:06:59ZBurn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation10.1038/s41598-017-07011-32045-2322https://doaj.org/article/afe79a61568341ec8376c8fb9c5a6d312017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07011-3https://doaj.org/toc/2045-2322Abstract 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.Harumasa NakazawaKazuhiro IkedaShohei ShinozakiMasayuki KobayashiYuichi IkegamiMing FuTomoyuki NakamuraShingo YasuharaYong-Ming YuJ. A. Jeevendra MartynRonald G. TompkinsKentaro ShimokadoTomoko YorozuHideki ItoSatoshi InoueMasao KanekiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Harumasa Nakazawa Kazuhiro Ikeda Shohei Shinozaki Masayuki Kobayashi Yuichi Ikegami Ming Fu Tomoyuki Nakamura Shingo Yasuhara Yong-Ming Yu J. A. Jeevendra Martyn Ronald G. Tompkins Kentaro Shimokado Tomoko Yorozu Hideki Ito Satoshi Inoue Masao Kaneki Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation
description	Abstract 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	article
author	Harumasa Nakazawa Kazuhiro Ikeda Shohei Shinozaki Masayuki Kobayashi Yuichi Ikegami Ming Fu Tomoyuki Nakamura Shingo Yasuhara Yong-Ming Yu J. A. Jeevendra Martyn Ronald G. Tompkins Kentaro Shimokado Tomoko Yorozu Hideki Ito Satoshi Inoue Masao Kaneki
author_facet	Harumasa Nakazawa Kazuhiro Ikeda Shohei Shinozaki Masayuki Kobayashi Yuichi Ikegami Ming Fu Tomoyuki Nakamura Shingo Yasuhara Yong-Ming Yu J. A. Jeevendra Martyn Ronald G. Tompkins Kentaro Shimokado Tomoko Yorozu Hideki Ito Satoshi Inoue Masao Kaneki
author_sort	Harumasa Nakazawa
title	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_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_sort	burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of hif-1α and mtorc1: role of protein farnesylation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/afe79a61568341ec8376c8fb9c5a6d31
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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

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