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Body and mind

Researchers pursue the molecular elixir of exercise

Exercise is healthy, is good for the body and helps us to live longer. Nevertheless, many people do not exercise in their busy and sedentary daily lives. This has caused the numbers of people who are overweight and who have type 2 diabetes to skyrocket. Researchers are now tracking the molecular fingerprint exercise leaves on our body. They hope to understand how exercise keeps the body young and healthy and whether an elixir exists for people’s lack of exercise.

Accelerated ageing and type 2 diabetes have many similarities: weakened metabolism, reduced insulin sensitivity and especially muscle atrophy. Similarly, exercise training and other forms of physical activity are part of the cure for these conditions, but why? Researchers are trying to answer this question to provide new opportunities for preventing and treating the side-effects of both ageing and type 2 diabetes.

“The basic question is how people keep their muscles healthy and strong. We know that exercise helps, but we do not know which molecular signals exercise releases and how these affect the muscles. The answers will help fill a gap in treatment because so many people cannot exercise for either mental or physical reasons. If we can trace the molecular causes for how exercise positively affects muscles, we may be able to treat these people by replicating the effects of exercise pharmaceutically,” explains Juleen R. Zierath, Professor, Karolinska Institutet, Stockholm, Sweden and Scientific Director, Novo Nordisk Foundation Center for Basic Metabolic Research.

Genes in action

Juleen R. Zierath’s previous research has shown that physical activity can prevent and treat type 2 diabetes because exercise promotes the muscles’ ability to respond to insulin and thus their ability to transport and metabolize glucose. For many years, the precise interaction between insulin, glucose and muscle cells among both healthy individuals and people with type 2 diabetes was a mystery.

“We now have numerous precise descriptions of many of the signalling pathways through which glucose is transported into the cells of healthy people. And we have shown that these pathways are blocked among people with type 2 diabetes, but new pathways open up after an exercise programme and weight loss. We now want to advance these findings to the molecular and genetic levels and hope that this will enable us to describe precisely how exercise affects muscle health.”

The future research will initially be carried out in the laboratory, where the researchers will examine the genetic profile of muscle cells and how stimulation with electrodes affects this profile. This method will reveal whether the gene expression in the muscle cells changes and whether the muscles transmit signals to their surroundings while they work. Eventually, however, the experiment has to be moved into the human body.

“The experiments with muscle cells will provide basic knowledge on the effect of stimulating the muscles. The situation will become far more complex when we subsequently examine biopsies of the muscles taken from the people participating in the experiment. We will also investigate whether exercise makes epigenetic modifications to DNA that help to determine which part of the genome is expressed.”

The molecular expression of exercise

Juleen R. Zierath’s recent research has focused on how exercise affects the human epigenome. Surprisingly, one thing the research showed was that the epigenome changes in the muscles of overweight people who have type 2 diabetes when they lose weight after bariatric surgery. Exercise is expected to have the same effect.

“This means that people’s destiny is not solely determined by their DNA. Although you inherit your DNA from your parents, you can still optimize your health by changing your lifestyle. So although genes comprise the factor with the greatest influence on disease and health, how we lead our lives reveals the genetic susceptibility.”

The researchers plan to monitor 100 participants to examine how exercise training affects their genes and muscles and whether the type of exercise that works best may differ for each individual participant.

“People are different – both physically and mentally, and exercise training therefore needs to be tailored for each person. Just as the regimen for a distance runner differs vastly from that of a sprinter, the type of exercise training that best suits an individual’s molecular fingerprint also differs greatly.”

This link between the basic science aspect of the research and the practical and specific applications in both prevention and treatment is very important for Juleen R. Zierath, who wants to help some of the 415 million people with diabetes who have no immediate prospect of a cure in the near future.

“Doctors can use this new molecular insight into the effects of exercise to identify people at risk of developing metabolic or muscle diseases. It can be used to optimize exercise training programmes and will hopefully also eventually lead to developing new types of treatments that can promote healthy ageing and prevent metabolic diseases,” concludes Juleen R. Zierath.

The limits of exercise physiology: from performance to health” has been published in Cell Metabolism. Juleen R. Zierath is Scientific Director of the Novo Nordisk Foundation Center for Basic Metabolic Research. In 2017, the Novo Nordisk Foundation awarded her an Advanced Grant for the project Integrative Biology of Exercise.

Juleen Zierath
Scientific Director, Professor
Juleen Zierath's research focuses on cellular mechanisms underlying the development of insulin resistance in Type 2 Diabetes (T2DM). The overarching goal of her group is to identify and validate molecular targets that prevent or treat skeletal muscle insulin resistance in T2DM. Her group is taking a translational approach to resolve the mechanism for peripheral insulin resistance using cell-based systems, genetically modified animal models, and clinical material from T2DM patients. In particular, Juleen Zierath's group is investigating if synchronizing exercise and nutrient interventions to the molecular circadian clock can maximize the health promoting benefit of these interventions, to enhance insulin sensitivity and prevent T2DM. Juleen Zierath's has experimentally de-convoluted the complex interaction between distinct insulin signaling pathways that modulate divergent downstream metabolic and gene regulatory responses in skeletal muscle. She has published more than 210 research papers and 70 review articles, with key discoveries published in Science, Cell, Nature Genetics, and Cell Metabolism.