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WHEN YOU EXERCISE, YOUR CELLS ARE TALKING TO EACH OTHER  
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Sneha Khedkar
January 3, 2025
The Scientist
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_ How does exercise benefit health? Molecules called exerkines partly
regulate its effects and provide therapeutic targets to mimic the
benefits of exercise. _

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On a brisk afternoon in March 2009 in Ontario, as winter melted into
spring, Mark Tarnopolsky
[[link removed]] and his team at
McMaster University sat around a table for their weekly lab meeting.
The topic was the focus of their group research: exercise
physiology. 

“I’ve been interested in exercise because I’m an athlete,”
said Tarnopolsky, who has competed internationally in sports such as
adventure racing, ski-orienteering, and winter triathlon. “And as a
neurologist who treats children and adults who have muscular dystrophy
or mitochondrial disease, I've always been very interested in how
exercise could provide benefit.”

In the lab meeting, as Tarnopolsky and his team discussed the diverse
molecules secreted from different tissues—myokines by muscles and
adipokines by fat tissue—that partly help mediate exercise effects,
Tarnopolsky had an idea.

“I said, geez, you know, really, we don't know where they're coming
from. Sometimes muscle, sometimes liver, sometimes fat,” recalled
Tarnopolsky. “Why don't we just call them ‘exerkines’ to sort of
broadly describe the proteins, the metabolites, and the microRNA that
change in response to exercise, which confer the systemic benefits?”

Today, researchers recognize exerkines
[[link removed]] as a broad
variety of signaling molecules—including peptides and proteins,
hormones, metabolites, lipids, and nucleic acids—released upon
exercising.1 These compounds exert their effects on target cells and
drive the whole-body effects of exercise. 

Tarnopolsky and other experts believe that uncovering the global
dynamics of exerkines can help them understand the physiological
effects of exercise, such as preventing or delaying diseases
[[link removed]] and improving
clinical outcomes in patients.2 Indeed, using both preclinical models
and studies in a few human volunteers, Tarnopolsky and others have
shown that exerkines can help delay aging, manage metabolic diseases
like diabetes and obesity, reduce the risk of cardiovascular diseases,
and improve cognition.

Although the team coined the term exerkine in 2009 and
first published [[link removed]] it
in 2016, scientists had long recognized that circulating humoral
factors mediate the benefits of exercise, at least in part.3 

“The first exerkine has been thought to be lactate,” said Lisa
Chow [[link removed]], an endocrinologist who
studies the effect of exercise on metabolic disorders at the
University of Minnesota. 

SKELETAL MUSCLE AS AN EXERKINE-SECRETING TISSUE

Over a century ago, scientists found that the muscles of exhausted
animals including mammals, birds
[[link removed]],
and amphibians
[[link removed]] secreted
lactate.4,5  Although initially thought of as metabolic waste,
researchers have shown that exercise-induced lactate
[[link removed]] can confer
systemic benefits.6 

Since muscles play an important role in exercise, scientists
hypothesized that factors secreted by muscles—myokines—formed the
molecular basis of exercise-induced changes. In 2000, researchers
measured the plasma cytokine levels in volunteers who exercised and
discovered that contracting muscles secreted interleukin-6
[[link removed]] (IL-6),
identifying it as the first myokine.7  “Since that time there's
just been an explosion of exerkines,” noted Chow.

With increasing interest in the field, scientists sought to
investigate the molecules underlying the effects of exercise. They
used both mouse models and a small number of human participants to
identify exerkines, the tissues that secrete them, and the cells they
target. Using these approaches, several research groups independently
showed that exercise triggers molecular and cellular changes—such as
altered calcium levels, change in pH, and hypoxia—in tissues.2 This
causes a cascade of events that eventually results in the tissues
releasing exerkines, which act on distinct target cells.

EXERKINES ACT ON CELLS OF THEIR ORIGIN, NEARBY, AND DISTANT CELLS

Some exerkines act in an autocrine manner on the tissues that secrete
them. For instance, when researchers probed the role of some
muscle-derived exerkines like IL-6
[[link removed]] and apelin
[[link removed]] using mouse
models, they discovered that these molecules improve metabolism,
promote mitochondrial biogenesis, or act on stem cells to enhance
muscle function.8,9

Soon after establishing IL-6 as a myokine, the group that made this
discovery injected it in humans to determine its mode of action. Their
studies revealed its paracrine effect—on cells surrounding the
tissue of origin—as it increased lipid breakdown
[[link removed]] in
adipose tissue.10  Around the same time, other research groups
showed that several other exerkines have a paracrine effect on nearby
tissues. 

Aside from autocrine and paracrine functions, researchers have found
that exerkines can also act on distant organs. During their studies,
Tarnopolsky and his team observed that people who exercised had better
skin than those with sedentary habits. They obtained biopsies from
volunteers to investigate the molecular mechanism behind this. “When
you did the skin biopsy with the punch in the athletes, it was
crunching [like] an apple, like it felt firm,” recalled Tarnopolsky.
“[While] in the sedentary people, the biopsy needle would twist and
spin because the dermis was not very intact.”

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

Skin is not the only distant tissue that muscle-derived exerkines act
on. Recent experiments with animal models revealed that exerkines such
as irisin [[link removed]] drive
the cognitive benefits of exercise by acting on cells in the nervous
system.12

LIVER, BONES, AND FAT TISSUES ALSO SECRETE EXERKINES

As interest in the field grew, studies from humans, mouse models and
cultured cells provided an important insight about these molecules:
Tissues other than the muscle secreted exerkines. 

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

These discoveries highlight that multiple organ systems produce
exerkines and are influenced by them, which may contribute to the
highly variable response to exercise. Exerkines, at least in part,
mediate this immensely complex inter-organ crosstalk, which ultimately
lead to the systemic effects of exercise. 

EXERKINES IN THE CLINIC AND HUMAN HEALTH

Understanding the role of exerkines can provide clarity about what
drives the overall health benefits of exercise. In addition to this,
Chow believes that profiling exerkines in people can provide a
personalized medicine approach to exercise. “We do know that people
have different responsiveness to exercise,” she said. While some
people benefit from a particular form of exercise
[[link removed](23)00476-X],
it may not have an effect on others.13 Understanding which exerkines
people will benefit from can help physicians tailor training programs
accordingly, or predict the result of practicing a particular exercise
form, she said. 

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

In contrast to pharmacological therapies, exercise effects are not
restricted to a specific target, so pinpointing one potentially
helpful molecule is unrealistic, he noted. “To mimic exercise, I
don't think a single molecule is going to cut it. It's not IL-15,
it's not IL-6, it's not apelin, it's not irisin, it's everything
together in the context of exercise.”

Although this can be valuable for people who are limited in their
exercise capacity or those with diseases, Tarnopolsky believes that
‘exercise in a pill’ is a myth. Nature has selected for exercise
to confer a biological advantage and trying to capture the benefits of
exercise in a single molecule would be going against millions of years
of evolution, he said. “I think you’re going to have a hard time
beating it.”

_Sneha Khedkar is an Assistant Editor at The Scientist. She has a
Master's degree in biochemistry and has written for Scientific
American, New Scientist, and Knowable Magazine, among others._

_The Scientist [[link removed]] delivers
monthly bite-sized interactive stories in the TS Digest, newsletters,
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* Chow LS, et al. Exerkines in health, resilience and disease
[[link removed]]. _Nat Rev
Endocrinol_. 2022;18(5):273-289.
* Walzik D, et al. Molecular insights of exercise therapy in
disease prevention and treatment
[[link removed]]. _Signal
Transduct Target Ther_. 2024;9(1):138.
* Safdar A, et al. The potential of endurance exercise-derived
exosomes to treat metabolic diseases
[[link removed]]. _Nat Rev
Endocrinol_. 2016;12(9):504-517.
* Kompanje EJO, et al. The first demonstration of lactic acid in
human blood in shock by Johann Joseph Scherer (1814–1869) in January
1843
[[link removed]]. _Intensive
Care Med_. 2007;33(11):1967-1971.
* Fletcher WM, Hopkins FG. Lactic acid in amphibian muscle
[[link removed]]. _J
Physiol_. 1907;35(4):247-309.
* Li VL, et al. An exercise-inducible metabolite that suppresses
feeding and obesity
[[link removed]]. _Nature_.
2022;606(7915):785-790.
* Steensberg A, et al. Production of interleukin-6 in contracting
human skeletal muscles can account for the exercise-induced increase
in plasma interleukin-6
[[link removed]]. _J
Physiol_. 2000;529(1):237-242.
* Knudsen JG, et al. Skeletal muscle IL-6 regulates muscle
substrate utilization and adipose tissue metabolism during recovery
from an acute bout of exercise
[[link removed]]. _PLoS
ONE_. 2017;12(12):e0189301.
* Vinel C, et al. The exerkine apelin reverses age-associated
sarcopenia [[link removed]]. _Nat
Med_. 2018;24(9):1360-1371.
* van Hall G, et al. Interleukin-6 stimulates lipolysis and fat
oxidation in humans
[[link removed]]. _ J
Clin Endocrinol Metab_. 2003;88(7):3005-3010.
* Crane JD, et al. Exercise-stimulated interleukin-15 is controlled
by AMPK and regulates skin metabolism and aging
[[link removed]]. _Aging
Cell_. 2015;14(4):625-634.
* Islam MR, et al. Exercise hormone irisin is a critical regulator
of cognitive function
[[link removed]]. _Nat Metab_.
2021;3(8):1058-1070.
* Noone J, et al. Understanding the variation in exercise responses
to guide personalized physical activity prescriptions
[[link removed]]. _Cell Metab_.
2024;36(4):702-724.

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