Exercise and muscle training have many benefits. They prevent cancer and cardiovascular disease, and they stabilize blood glucose levels among people with type 2 diabetes. This is one reason why researchers have been trying for decades to understand how physical activity confers so many benefits. New research reveals the molecular mechanisms involved, and the researchers hope that people who have difficulty exercising can be stimulated artificially so that they can still enjoy the many useful health benefits.
A rising pulse, beads of sweat and more rapid breathing. Although exercise is tough, we know it is good for us, but we are not sure why. For decades, researchers have tried to understand the molecular mechanisms that trigger major metabolic responses in muscles that help to optimize athletic performance and to prevent and treat ageing- and lifestyle-related diseases, such as type 2 diabetes.
“Unlike healthy people, people with type 2 diabetes cannot rely on insulin getting the muscles to take up glucose. If they exercise, however, the glucose is transported through glucose transporter type 4 (GLUT-4). However, we are only now beginning to understand through our new experiments how muscle contractions stimulate that transport. Now we hope to find a way to artificially stimulate these same mechanisms so that we can help people who are not physically able to exercise,” explains Thomas E. Jensen, research group leader and Associate Professor, Department of Nutrition, Exercise and Sports, University of Copenhagen.
Crucial link to health effects
Researchers have been on a long and complicated search for the mechanisms that give exercise the same stabilizing effect on blood glucose as insulin among people with type 2 diabetes. For more than 60 years, researchers have been trying to understand how glucose is transported into the muscles, since this is a key factor in keeping blood glucose levels low. Insulin helps this process among people without diabetes. However, for people with diabetes, either insulin does not work optimally (insulin resistance) or the body does not produce enough insulin, and the muscles require other mechanisms.
“Our goal was therefore to try to understand the insulin-dependent transport of glucose through GLUT-4: how does an intact organism using muscles during physical activity stimulate this transport? Laboratory experiments on muscle tissue grown outside the body have shown that reactive oxygen species, including free radicals, are important signals for increasing transport. However, investigating whether this is also the case when muscles are functioning normally inside the body and the origin of these reactive oxygen species has been difficult technically.”
The researchers therefore adopted new techniques to investigate these mechanisms in mice and humans. By combining advanced microscopy, genetic biosensors, genetically modified mouse models and muscle biopsies from people, they examined for the first time the relationship between glucose uptake in muscles and the various probable sources for producing reactive oxygen species during exercise corresponding to a brisk 20- to 30-minute run.
“We especially focused on the NADPH oxidase 2 (NOX2) enzyme, which produces the reactive oxygen species. Exercise increased the production of reactive oxygen species through NOX2 in mice and among people. However, when we removed NOX2 in mice, the mice also lost the positive effects of exercise on glucose uptake. So, during moderate physical activity, the NOX2 enzyme is the primary source of production of the reactive oxygen species that are necessary for transporting glucose into the muscle cells.”
Reactive oxygen species must be tamed
The researchers managed to determine the precise molecular details of the beneficial effects of exercise on stabilizing blood glucose in even greater detail. For example, they discovered that the NOX2 enzyme works only in the presence of two other proteins, Rac1 and p47phox, and this knowledge may prove to be the key to making the new research useful.
“Learning to understand why and especially to simulate how physical activity helps people with diabetes, cardiovascular disease or cancer requires understanding the tiny details. They will be key in finding the targets for future medicines so that we can help the people who cannot exercise to get its beneficial effects.”
However, if the targets for future medicines have too central a role in the body, the medicines may have not only positive effects but also other negative side-effects. For example, researchers already know that the production of the same reactive oxygen species that benefit adapting to physical activity is chronically elevated among people who have several specific diseases. These reactive oxygen species can damage cells and even destroy them if they are not tamed in the body.
“Hormesis is a concept in which a minor stress effect, here in the form of increasing reactive oxygen species during exercise, triggers several adaptations that improve health. Conversely, the excessive production of reactive oxygen species – oxidative stress – contributes to several diseases and perhaps even ageing, which explains why people take antioxidants that eliminate reactive oxygen species. Surprisingly, regular exercise also strengthens many of the body’s own antioxidant mechanisms, providing resistance to oxidative stress. The new breakthrough is that we can now distinguish between the different sources of reactive oxygen species in muscle cells inside the body instead of just examining the whole cell. More detailed understanding is an important step towards fundamentally understanding how reactive oxygen species contribute to health and disease. In the long term, this may enable the development of drugs that stimulate some of the positive effects of exercise.”
“Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise” has been published in Nature Communication. In 2015, the Novo Nordisk Foundation awarded a grant to Thomas E. Jensen for the project Understanding Skeletal Muscle Plasticity in Health and Disease. In 2019, the Independent Research Fund Denmark and Danish Diabetes Academy awarded grants to enable him to continue his research.
