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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.

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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Nakazawa H, Ikeda K, Shinozaki S, Kobayashi M, Ikegami Y, Fu M, Nakamura T, Yasuhara S, Yu YM, Martyn JAJ, Tompkins RG, Shimokado K, Yorozu T, Ito H, Inoue S, Kaneki M,


Nakazawa H, Ikeda K, Shinozaki S, Kobayashi M, Ikegami Y, Fu M, Nakamura T, Yasuhara S, Yu YM, Martyn JAJ, Tompkins RG, Shimokado K, Yorozu T, Ito H, Inoue S, Kaneki M, (click to view)

Nakazawa H, Ikeda K, Shinozaki S, Kobayashi M, Ikegami Y, Fu M, Nakamura T, Yasuhara S, Yu YM, Martyn JAJ, Tompkins RG, Shimokado K, Yorozu T, Ito H, Inoue S, Kaneki M,

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Scientific reports 2017 07 267(1) 6618 doi 10.1038/s41598-017-07011-3
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.

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