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

doi:10.1126/sciadv.abl4988

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

Sci Adv. 2021 Dec 17;7(51):eabl4988. doi: 10.1126/sciadv.abl4988. Epub 2021 Dec 15.

Authors

Chrysovalantou E Xirouchaki^{1

2}, Yaoyao Jia^{1

2}, Meagan J McGrath^{1

2}, Spencer Greatorex^{1

2}, Melanie Tran^{1

2}, Troy L Merry^{1

2

3}, Dawn Hong^{1

2}, Matthew J Eramo^{1

2}, Sophie C Broome³, Jonathan S T Woodhead³, Randall F D'souza³, Jenny Gallagher^{1

2}, Ekaterina Salimova⁴, Cheng Huang^{1

2

5}, Ralf B Schittenhelm^{1

2

5}, Junichi Sadoshima⁶, Matthew J Watt^{1

7}, Christina A Mitchell^{1

2}, Tony Tiganis^{1

2

8}

Affiliations

¹ Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
² Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
³ Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
⁴ Monash Biomedical Imaging, Monash University, Clayton, Victoria 3800, Australia.
⁵ Monash Proteomics and Metabolomics Facility, Monash University, Clayton, Victoria 3800, Australia.
⁶ Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
⁷ Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
⁸ Monash Metabolic Phenotyping Facility, Monash University, Clayton, Victoria 3800, Australia.

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.