Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance

Journal article


Xirouchaki, Chrysovalantou E., Jia, Yaoyao, McGrath, Meagan J., Greatorex, Spencer, Tran, Melanie, Merry, Troy L., Hong, Dawn, Eramo, Matthew J., Broome, Sophie C., Woodhead, Jonathan S. T., D'souza, Randall F., Gallagher, Jenny, Salimova, Ekaterina, Huang, Cheng, Schittenhelm, Ralf B., Sadoshima, Junichi, Watt, Matthew J., Mitchell, Christina A. and Tiganis, Tony. (2021). Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance. Science Advances. 7(51), p. Article eabl4988. https://doi.org/10.1126/sciadv.abl4988
AuthorsXirouchaki, Chrysovalantou E., Jia, Yaoyao, McGrath, Meagan J., Greatorex, Spencer, Tran, Melanie, Merry, Troy L., Hong, Dawn, Eramo, Matthew J., Broome, Sophie C., Woodhead, Jonathan S. T., D'souza, Randall F., Gallagher, Jenny, Salimova, Ekaterina, Huang, Cheng, Schittenhelm, Ralf B., Sadoshima, Junichi, Watt, Matthew J., Mitchell, Christina A. and Tiganis, Tony
Abstract

Reactive oxygen species (ROS) generated during exercise are considered integral for the health-promoting effects of exercise. However, the precise mechanisms by which exercise and ROS promote metabolic health remain unclear. Here, we demonstrate that skeletal muscle NADPH oxidase 4 (NOX4), which is induced after exercise, facilitates ROS-mediated adaptive responses that promote muscle function, maintain redox balance, and prevent the development of insulin resistance. Conversely, reductions in skeletal muscle NOX4 in aging and obesity contribute to the development of insulin resistance. NOX4 deletion in skeletal muscle compromised exercise capacity and antioxidant defense and promoted oxidative stress and insulin resistance in aging and obesity. The abrogated adaptive mechanisms, oxidative stress, and insulin resistance could be corrected by deleting the H2O2-detoxifying enzyme GPX-1 or by treating mice with an agonist of NFE2L2, the master regulator of antioxidant defense. These findings causally link NOX4-derived ROS in skeletal muscle with adaptive responses that promote muscle function and insulin sensitivity.

Year2021
JournalScience Advances
Journal citation7 (51), p. Article eabl4988
PublisherAmerican Association for the Advancement of Science (AAAS)
ISSN2375-2548
Digital Object Identifier (DOI)https://doi.org/10.1126/sciadv.abl4988
PubMed ID34910515
Scopus EID2-s2.0-85121999594
PubMed Central IDPMC8673768
Open accessPublished as ‘gold’ (paid) open access
Page range1-24
FunderNational Health and Medical Research Council (NHMRC)
Diabetes Australia
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online15 Dec 2021
Publication process dates
Accepted26 Oct 2021
Deposited17 Jan 2023
Grant IDAPP1162798
APP1082253
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