Effects of acute hypoxia exposure with different durations on activation of Nrf2-ARE pathway in mouse skeletal muscle

Ji, Weixiu and Wang, Linjia and He, Shiyi and Yan, Lu and Li, Tieying and Wang, Jianxiong and Kong, Ah-Ng Tony and Yu, Siwang and Zhang, Ying (2018) Effects of acute hypoxia exposure with different durations on activation of Nrf2-ARE pathway in mouse skeletal muscle. PLoS One, 13 (12). pp. 1-15.

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Abstract

Background Hypoxia training enhances the endurance capacity of athletes. This response may in part be attributed to the hypoxia-induced increase in antioxidant capacity in skeletal muscles. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor which regulates the expression of genes via binding to the antioxidant-response element (ARE) of these genes, plays a crucial role in stimulating the body’s defense system and potentially responds to hypoxia. Meanwhile, hypoxia-inducible factor-1α (HIF-1α) is an important player in protecting cells from hypoxic stress. The purpose of this study was to investigate the effects of acute hypoxia exposure with different durations on the activation of Nrf2-ARE pathway and a possible regulatory role of HIF-1α in these responses. Methods C57BL/6J mice were allocated into the non-hypoxia 0-hour, 6-hour, 24-hour, and 48-hour hypoxic exposure (11.2% oxygen) groups. The quadriceps femoris was collected immediately after hypoxia. Further, to investigate the possible role of HIF-1α, C2C12 myoblasts with HIF-1α knockdown by small interfering RNA (siRNA) and the inducible HIF-1α transgenic mice were employed. Results The results showed that 48-hour hypoxia exposure up-regulated protein expression of Nrf2, Nrf2/ARE binding activity and the transcription of antioxidative genes containing ARE (Sod1 and others) in mouse skeletal muscle. Moreover, HIF-1α siRNA group of C2C12 myoblasts showed a remarkable inhibition of Nrf2 protein expression and nuclear accumulation in hypoxia exposure for 72 hours compared with that in siRNA-Control group of the cells. In addition, HIF-1α transgenic mice gave higher Nrf2 protein expression, Nrf2/ARE binding activity and expressions of Nrf2-mediated antioxidative genes in their skeletal muscle, compared with those in the wild-type mice. Conclusions The findings suggested that the acute hypoxia exposure could trigger the activation of Nrf2-ARE pathway, with longer duration associated with higher responses, and HIF-1α expression might be involved in promoting the Nrf2-mediated antioxidant responses in skeletal muscle. © 2018 Ji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: 'Copyright: ©2018 Ji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited' - Publisher.
Faculty / Department / School: Current - Faculty of Health, Engineering and Sciences - School of Health and Wellbeing
Date Deposited: 25 Jan 2019 03:47
Last Modified: 05 Feb 2019 02:22
Uncontrolled Keywords: hypoxia inducible factor 1alpha; small interfering RNA; transcription factor Nrf2; animal cell; antioxidant responsive element; binding affinity; C2C12 cell line; controlled study; disease duration; exposure; gene; gene activation; gene knockdown; hypoxia; male; mouse; nonhuman; protein expression; quadriceps femoris musc le; signal transduction; skeletal muscle; transgenic mouse; upregulation
Fields of Research : 06 Biological Sciences > 0601 Biochemistry and Cell Biology > 060104 Cell Metabolism
11 Medical and Health Sciences > 1106 Human Movement and Sports Science > 110602 Exercise Physiology
Socio-Economic Objective: E Expanding Knowledge > 97 Expanding Knowledge > 970106 Expanding Knowledge in the Biological Sciences
E Expanding Knowledge > 97 Expanding Knowledge > 970111 Expanding Knowledge in the Medical and Health Sciences
Identification Number or DOI: 10.1371/journal.pone.0208474
URI: http://eprints.usq.edu.au/id/eprint/35261

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