Physical inactivity can lead to several diseases, such as type 2 diabetes, especially in an aging population. Although the benefits of physical activity or exercise are indisputable, the precise mechanisms by which physical activity promotes metabolic health are not fully understood.

In a recent study, investigators led by Tony Tiganis at Monash University, Australia have identified that upregulation of the enzyme NOX4 (NADPH oxidase 4) boosted levels of reactive oxygen species (ROS) and protected development of insulin resistance in both aged as well as obese mice.

The team reported its results in the December 16, 2021, online issue of Science Advances.

Physical exercise induces higher mitochondrial content levels, leading to greater glucose uptake by muscles. It is well known that exercise promotes glucose uptake and increases skeletal muscle insulin sensitivity. However, it is not understood how precisely exercise drives mitochondrial biogenesis. Previously, Tiganis and his team had showed that ROS in the form of hydrogen peroxide could enhance insulin sensitivity after exercise and attenuate high fat diet-induced insulin resistance. In the current study, Tiganis' team shows that physical exercise led to increased levels of NOX4 that, in turn, led to generation of hydrogen peroxide and ROS and the induction of NFE2L2 (nuclear factor erythroid 2-related factor 2). NFE2L2 induced the expression of antioxidant response element (ARE)-driven genes that promoted mitochondrial biogenesis.

According to senior author Tiganis, who is a professor at Monash University and heads the Monash Biomedicine Discovery Institute Metabolism, Diabetes and Obesity Program, the "exercise-induced ROS driven adaptive responses are integral to the health-promoting effects of exercise." In their Science Advances paper, the authors wrote that their findings demonstrate that "the generation of ROS by skeletal muscle NOX4 prevents oxidative damage, maintains muscle function and exercise capacity, and attenuates the age- and obesity-associated development of insulin resistance."

ROS is produced in skeletal muscle as a matter of course, but it declines with age, which the researchers say helps drive the development of insulin resistance. The study showed that concentrations of NOX4 in skeletal muscle were directly related to aging and a decline in insulin sensitivity. The authors found that skeletal muscle NOX4 expression declined in aged sedentary mice and in obese mice. Importantly, the scientists show that the levels of NOX4 in skeletal muscle are directly related to age-associated decline in insulin sensitivity. "In this study we have shown, in animal models, that skeletal muscle NOX4 abundance is decreased with aging and that this leads to a reduction in insulin sensitivity," Professor Tiganis said.

To further confirm the findings, the authors deleted Nox4 in muscle which then exacerbated insulin resistance in obesity and nullified the beneficial effects of exercise on insulin sensitivity. These effects were attributed to reductions in hydrogen peroxide, defective NFE2L2-mediated antioxidant defense, and mitochondrial oxidative stress which over time diminished the insulin response and contributed to the development of insulin resistance.

Treatment of skeletal muscle cells with the NFE2L2 agonist sulforaphane not only restored the decreased antioxidant defense gene expression but also restored insulin signaling in NOX4-deficient myoblasts. The authors also report that NOX4 expression was also increased in human muscle 3-4 hours following acute high-intensity interval training. As expected, the increased NOX4 expression after exercise was accompanied by an increased expression of the gene encoding the transcription factor NFE2L2, the master regulator of antioxidant defense. Tiganis believes that the implication of NOX4 in promoting insulin sensitivity can offer new targets for potential drugs that protect against consequences of aging. "Triggering the activation of the adaptive mechanisms orchestrated by NOX4 with drugs might ameliorate key aspects of aging, including the development of insulin resistance and type 2 diabetes," Tiganis said. "One of these compounds, sulforaphane, is found naturally, for instance, in cruciferous vegetables, such as broccoli or cauliflower, though the amount needed for antiaging effects might be more than many would be willing to consume," he added.