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

作者：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

来源：Scientific Reports, 2017, 7(1): 6618.

DOI：10.1038/s41598-017-07011-3

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)-1 alpha, 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-1 alpha 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.

• 出版日期2017-7-26