Scientists at Monash University have discovered an enzyme, NOX4, which may be key to the health-boosting benefits of exercise, particularly as we age. One of the main reasons for the increased prevalence of type 2 diabetes with age is the development of insulin resistance, and this is often caused by reduced physical activity as we age. The new research in mice has uncovered how physical activity induces NOX4 in skeletal muscle, which is involved in the mechanisms that enhances insulin responsiveness and in turn promote metabolic health.

Importantly, the enzyme could feasibly be targeted by drugs, to protect against consequences of aging such as muscle wasting and diabetes. “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,” said research lead Tony Tiganis, PhD,” at Monash University Biomedicine Institute (BDI).

Tigianis and colleagues reported on their findings in Science Advances, in a paper titled, “Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance,” in which they concluded, “In this study, we demonstrate that the generation of ROS by skeletal muscle NOX4, the expression of which is increased by exercise and conversely is reduced with age or obesity, induces adaptive responses that prevent oxidative damage, maintain muscle function and exercise capacity, and attenuate the age- and obesity-associated development of insulin resistance.”

The Monash University team suggests that the proportion of people worldwide over 60 years of age will double in the next three decades, and by 2031 more than six million people in Australia will be more than 65 years old. The incidence of type 2 diabetes increases with age so this aging population will also result in an increased incidence of the disease globally.

Over the course of evolution, exercise in the form of food gathering, building shelters, or avoiding predators, has been essential for human survival, and this has required the development of adaptive mechanisms to support muscle function and overall health, the authors explained. However, in modern times, technology has given us less need for physical activity in order to survive. And as the authors pointed out, “Physical inactivity contributes to the development of a myriad of human diseases, including insulin resistance and type 2 diabetes, that have reached epidemic proportions throughout the world.”

Yet while the benefits of physical activity or exercise are irrefutable, the team continued, “… the precise mechanisms by which physical activity promotes metabolic health are incompletely understood.” Exercise exposes skeletal muscles to acute stresses, which then stimulate compensatory and adaptive physiological responses. These adaptations then increase tolerance and protect against future stresses. “These favorable adaptation to stressors that would otherwise be harmful at higher doses is known as “hormesis.”

The latest research by Tiganis and colleagues now suggest that reductions in reactive oxygen species (ROS) production during aging is instrumental in the development of insulin resistance According to Tiganis, skeletal muscle constantly produces ROS and this is increased during exercise. “Exercise-induced ROS drives adaptive responses that are integral to the health-promoting effects of exercise,” he said. As the authors noted in their paper, “The production of ROS in response to acute bouts of exercise or chronic exercise training is considered essential for the adaptive responses necessary to meet the energy demands of exercise.”

The studies in mice have demonstrated how the enzyme NADPH oxidase 4 (NOX4) is essential for exercise-induced ROS and the adaptive responses that drive metabolic health. The experiments in mice found that NOX4 is increased in skeletal muscle after exercise, and that this then leads to increased ROS which elicits adaptive responses that protect the mice against developing insulin resistance, which otherwise occurs with aging or diet induced-obesity.

Importantly, the scientists showed 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 NOX 4 abundance is decreased with aging and that this leads to a reduction in insulin sensitivity,” Tiganis said. Their experiments also found that deleting NOX4 in muscle worsened the development of insulin resistance in obesity, and also reduced the beneficial effects of exercise on insulin sensitivity. “… the deletion of NOX4 in muscle not only exacerbates the development of insulin resistance with aging and obesity, but also diminishes the beneficial effects of acute exercise on insulin action,” they wrote. Collectively, they said, their findings “… are consistent with NOX4 deficiency in muscle abrogating the antioxidant defense response to promote mitochondrial oxidative stress and the development of insulin resistance.”

“The results of this study indicate that skeletal muscle NOX4 is instrumental in orchestrating hormetic responses that attenuate the age-associated development of insulin resistance, hyperinsulinemia, and hyperglycemia, hallmarks of type 2 diabetes,” the team further concluded. “Our findings underscore the importance of redox balance in metabolic health and provide important insight into pathophysiological mechanisms contributing to the diabetes epidemic in our aging and increasingly sedentary populations.”

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