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

Chrysovalantou E. Xirouchaki, Yaoyao Jia, Meagan J. McGrath, Spencer Greatorex, Melanie Tran, Troy L. Merry, Dawn Hong, Matthew J. Eramo, Sophie C. Broome, Jonathan S.T. Woodhead, Randall F. D'Souza, Jenny Gallagher, Ekaterina Salimova, Cheng Huang, Ralf B. Schittenhelm, Junichi Sadoshima, Matthew J. Watt, Christina A. Mitchell, Tony Tiganis

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)


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.

Original languageEnglish
Article numbereabl4988
Number of pages24
JournalScience Advances
Issue number51
Publication statusPublished - 17 Dec 2021

Cite this