Exerkines: Molecular messengers that mediate the effects of exercise

oA crisp afternoon in Ontario in March 2009, as winter melted into spring. Mark Tarnopolsky His team at McMaster University sits around a table for their weekly lab meeting. The topic was exercise physiology, the focus of the group’s research.

“I was interested in sports because I’m an athlete,” said Tarnopolsky, who competed internationally in sports including adventure racing, ski orienteering and winter triathlons. “And as a neurologist who treats children and adults with muscular dystrophies or mitochondrial diseases, I’ve always been very interested in how exercise can provide benefits.”

At a laboratory meeting, Tarnopolsky and his team discussed the different molecules secreted by different tissues (myokines by muscle, adipokines by adipose tissue) that help, in part, mediate the effects of exercise, bringing the idea to Tarnopolsky. I remembered it.

“I said, oh my gosh, really, we don’t know where they come from. Sometimes it’s muscle, sometimes it’s liver, sometimes it’s fat,” Tarnopolsky recalled. “What if we called them ‘exerkines’ to broadly describe the proteins, metabolites, and microRNAs that change in response to exercise and provide systemic benefits?”

Today, researchers Exerkin A variety of signaling molecules, including peptides and proteins, hormones, metabolites, lipids, and nucleic acids, released during exercise.¹ These compounds exert their effects on target cells and promote the systemic effects of exercise.

Tarnopolsky and other experts believe that uncovering the overall dynamics of exerkines could help us understand the physiological effects of exercise, such as: preventing or delaying disease Improve patient clinical outcomes.² In fact, Tarnopolsky and others have shown, through preclinical models and studies with small numbers of volunteers, that exerkines may help delay aging, manage metabolic diseases such as diabetes and obesity, reduce the risk of cardiovascular disease, and improve cognition. It showed that it can be done.

The team first coined the term exerkine in 2009. published In 2016, scientists have long recognized that circulating humoral factors mediate, at least in part, the benefits of exercise.³

“The first exerkine was thought to be lactic acid,” he said. Lisa Chowis an endocrinologist who studies the effects of exercise on metabolic disorders at the University of Minnesota.

Skeletal muscle as an exerkin secreting tissue

More than 100 years ago, scientists discovered that the muscles of tired animals, including mammals, birdsand amphibia Secreted lactic acid.^4,5 Initially thought to be metabolic waste, researchers found: lactic acid from exercise We can provide systematic benefits.⁶

Because muscles play an important role in exercise, scientists have hypothesized that myokines, factors secreted by muscles, form the molecular basis of exercise-induced changes. In 2000, researchers measured plasma cytokine levels in volunteers who exercised and found that contracting muscles secreted them. Interleukin-6 (IL-6), identifying it as the first myokine.⁷ “Since then, exercaine has exploded,” Chow said.

As interest in this field grows, scientists seek to investigate the molecules that underlie the effects of exercise. Using both a mouse model and a small number of human participants, they identified exerkines, the tissues that secrete them, and the target cells. Using this approach, several research groups have independently shown that exercise causes molecular and cellular changes, such as altered tissue calcium levels, pH changes, and hypoxia.² This sets off a chain of events that ultimately leads to the release of exerkines that act on distinct target cells in the tissue.

Exerkins act on the cell of origin, nearby cells, and distant cells.

Some exerkines act in an autocrine manner in the tissues that secrete them. For example, when researchers investigated the role of some muscle-derived exerkines: IL-6 and Apelin Using mouse models, they discovered that these molecules improve muscle function by improving metabolism, promoting mitochondrial biogenesis, or acting on stem cells.^8,9

Shortly after establishing IL-6 as a myokine, the group that made this discovery injected IL-6 into humans to determine its mode of action. Their study revealed a paracrine effect on cells surrounding the tissue of origin as it increases. lipolysis In adipose tissue.¹⁰ Around the same time, other research groups showed that several other exerkines had paracrine effects on nearby tissues.

In addition to autocrine and paracrine functions, researchers have discovered that exerkines can also act on distant organs. During the study, Tarnopolsky and his team observed that people who exercised had better skin than those with sedentary lifestyles. They obtained biopsies from volunteers to investigate the molecular mechanisms behind this. “When we did skin biopsies on athletes with punches, they were crunchy. [like] The apples felt solid,” Tarnopolsky recalled. “[While] “In sedentary people, the biopsy needle would twist and rotate because the dermis was intact.”

To investigate the molecular mechanisms underlying skin health in athletes, the team extracted blood from two groups of people. They found that exercise induces the secretion of . IL-15 From muscles.¹¹ When we treated skin fibroblasts with this exerkine, we observed an increase in mitochondrial biogenesis, which improved overall tissue health.

The skin is not the only distant tissue where muscle-derived exerkines act. Recent experiments in animal models have identified the following exerkines: Irisin It acts on cells of the nervous system to induce the cognitive benefits of exercise.¹²

Liver, bone, and adipose tissue also secrete exerkines

As interest in the field has grown, studies in humans, mouse models, and cultured cells have provided important insights into these molecules. Tissues other than exerkines secreted from muscles.

Independent studies have shown that tissues such as the liver, adipose tissue, bones, and brain secrete molecules in response to exercise. As researchers looked deeper into the effects of these molecules, they discovered that exerkines act on a variety of tissues, including the liver, intestines, heart, and organ systems such as the nervous, endocrine, and immune systems.¹

These findings highlight that multiple organ systems produce and are influenced by exerkines, which can contribute to very diverse responses to exercise. Exerkins mediate, at least in part, this incredibly complex organ-to-organ crosstalk, which ultimately leads to the systemic effects of exercise.

Exerkin in Clinics and Human Health

Understanding the role of exerkines provides clarity on what drives the overall health benefits of exercise. Beyond this, Chow believes that profiling people’s exerkines could provide a personalized medicine approach to exercise. “We know that people react differently to exercise,” she said. Some people special form of exerciseIt may not affect others.¹³ Understanding which exercises will help people can help doctors tailor training programs accordingly or predict the results of practicing a particular form of exercise, she said.

As researchers increasingly highlight the role and biological effects of exerkines, people have wondered whether these molecules could be harnessed to mimic the benefits of exercise in individuals. However, Tarnopolsky does not believe this is possible.

Unlike drug treatments, the effects of exercise are not limited to specific targets, making it unrealistic to pinpoint potentially helpful molecules, he noted. “I don’t think a single molecule would stop moving to mimic movement. It’s not IL-15, it’s not IL-6, it’s not Apelin, it’s not Irisin, it’s all together in the context of exercise.”

While this may be valuable for people with limited exercise capacity or medical conditions, Tarnopolsky believes ‘exercise through pills’ is nothing more than a myth. Nature selected exercise to confer biological advantages, he said, and trying to capture the benefits of exercise in a single molecule would go against millions of years of evolution. “I think you’ll be hard to beat.”