Introducing Exerkines: The Magical Molecules of Exercise. Everyone knows that exercise improves health. That’s old news. Here’s something far more exciting. Scientists have demonstrated that our skeletal muscles do much more than just move us about. While contracting, our muscles release swarms of molecules that spread throughout our bodies and blend with molecules released by other organs. These streams of hormone-like agents play a crucial role in mediating the beneficial effects of exercise. These sprightly chemicals have been shown to do everything from enhancing memories to warding off chronic diseases.

If you haven’t heard about these magical molecules, known as exerkines, don’t feel bad. According to my recent informal poll, most respondents (including physicians, nurses, physical therapists, and pharmacologists) had never heard the word, exerkines. This shocks me because the first exerkine was discovered over a quarter century ago. Since then, thousands upon thousands of scientific papers documenting the dramatic effects these molecules have been published.

Yet reports of these discoveries have been largely absent in the popular press. Why hasn’t the general public been informed about the therapeutic effects of these magical molecules? Why haven’t the astonishing benefits of exercise been loudly proclaimed?

The Healing Power of Exercise

This is not breaking news. Even 10 years ago, researchers were touting the significance of these findings. An article in JAMA Internal Medicine stated: “There is no medication treatment that can influence as many organ systems in a positive manner as can physical activity.”

Since then, evidence revealing the power of exercise has expanded. Regular exercise has been shown to reduce inflammation, improve metabolism, strengthen bones and muscles, sharpen cognitive performance, and support immune function. There’s more! Exercise lowers the risk of numerous chronic conditions such as type 2 diabetes, obesity, cardiovascular disease, osteoporosis, and even some cancers. Exercise has also been shown to have positive effects on such neurological conditions like dementia, depression, and Parkinson’s disease.

So, how exactly does exercise achieve its magical effects? How does it produce its amazing therapeutic results? That’s where the powerful science of exerkines comes in.

The Search for a Molecular Explanation

The idea that muscles might produce some kind of “exercise factor” goes back to the mid-20th century, when scientists first noticed that the benefits of physical activity extended far beyond the muscles themselves. But it took decades for the tools of modern molecular biology to catch up. Finally, in 2000, a research team in Copenhagen, while studying the immune system, discovered that contracting (but not resting) leg muscles secreted a molecule called interleukin-6 (IL-6), a cytokine known to mediate anti-inflammatory effects. This team had previously demonstrated that certain immune cells were mobilized in the blood of their subjects when pedaling on stationary bikes. They logically concluded that the release of IL-6 from the contracting leg muscles had caused the immune response.

That discovery sparked a global wave of interest. Scientists quickly demonstrated that our working muscles secrete a second cytokine, then a third. The Danish researchers coined the term myokines to describe these cytokines released from muscle cells (myo- meaning muscle). But myokines were just the beginning. The excitement grew.

From Myokines to Exerkines

 Researchers soon learned that other organs also secrete a variety of molecules during exercise. Those released from the heart were called cardiokines, from the liver hepatokines, and the brain neurokines, to mention only three of the other organs shown to secrete chemicals during exercise. Even today, researchers continue to identify additional molecules that are secreted when we exercise. To simplify references to the increasing number of “kines” shown to be released during exercise, a group of researchers coined the umbrella term, exerkines, which includes all biologically active molecules secreted during exercise, regardless of their origin.

The number of exerkines released during exercise is staggering. A 2023 review by Professor Bente Klarlund Pedersen, the Copenhagen researcher who led the original IL-6 study, reported that skeletal muscle alone can release over 650 different myokines. That’s not to imply that contributions from other organs aren’t also important. The total number of identified exerkines from all sources now exceeds 2,000.

How Exerkines Work

Secreted from cells located in numerous organs, exerkines may attach to receptors on the surface of the very cell secreting them, thus being able to alter that cell’s own behavior (autocrine function). They also can diffuse through intracellular fluids and attach to receptors on nearby cells, using this route to influence the cells surrounding the secreting cell (paracrine function). These molecules also enter the bloodstream and influence distant cells. (endocrine function). In effect, this multitude of exerkines operates at multiple sites during exercise and creates a remarkable chemical “network” throughout the body, a network that coordinates the healthful benefits of exercise.

To visualize the flow of exerkines set into motion by exercise, along with some of their widespread effects, glance at the accompanying figure. The featured image is from the same article.

The figure depicts the effects of a few of the many myokines released during exercise. Notice that certain myokines stimulate the release of GLP-1 from the gut. GLP-1 is the hormone popularly known as a stimulator of insulin secretion and thus valuable in the treatment of type 2 diabetes. It also inhibits appetite, making it valuable for weight management. When those effects were discovered, pharmaceutical companies took action. Drugs chemically similar to GLP-1 are now available by prescription. Such drugs as Ozempic and Wegovy produce effects similar to those caused by our natural GLP-1 hormone.

Researchers believe the conglomeration of molecules released during exercise must somehow be regulated. They postulate that this flood of chemicals must engage in an unrecognized form of “crosstalk” that enables them to interact and modulate one another’s effects. As of now, little is known of any such process, but unlocking the details of such communication could open doors in the fields of aging, memory loss, and chronic disease.

Exercise and the Brain: A Closer Look

Among the organs most profoundly affected by exerkines is the brain. One area of focus is the hippocampus, a deep-brain structure essential to memory and spatial navigation. In healthy older adults, hippocampal volume typically shrinks by 1–2% per year, a loss that may underlie those frustrating “senior moments.”

A pivotal study from the Salk Institute compared hippocampal changes in two groups of older adults (average age mid-60s). One group walked briskly for 40 minutes, three times per week. The other, a control group, performed only stretching and toning. After one year, MRI scans revealed that the control group experienced the expected decline of 1.4% in hippocampal volume, but the big surprise was in the exercise group. Those subjects responded quite differently. They actually increased their hippocampal volume by 2% during the year.

This striking result supports earlier findings that certain exerkines cross the blood-brain barrier and stimulate neurogenesis, the growth of new brain cells. Clearly, exercise can improve our brains.

Aerobic vs. Resistance Training: A Molecular Difference

 Given the often cited “wisdom of the body,” it’s not surprising that the blend of exerkines released is fine-tuned according to the type, intensity, and duration of exercise being performed. I think this is a spot to provide a glimpse of how detailed the science of exercise actually is.

So, I’ll quote a few brief segments from a 2024 review of the field in PeerJ 2024 April 29 by Zhou et al, titled Exploring exercise-driven exerkines: unraveling the regulation of metabolism and inflammation. The entire article is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC11064867/. (I’ve even deleted a few details in the short selection below.)

Exerkine secretion is intricately modulated by the intensity, type, and duration of exercise activity, resulting in a complex interplay of physiological responses. Moderate-intensity training is an effective exercise for increasing apelin levels, which can stimulate protein synthesis. . . Aerobic exercise significantly reduces the inflammatory load in type 2 diabetes by improving circulating levels of factors such as resistin, TNF-α, and IL-6. . . On the other hand, resistance training, characterized by high-intensity muscle contractions, suppresses the release of MSTN. (MSTN IS an abbreviation for myostatin, a negative regulator of muscle growth, so less MSTN promotes muscle growth and strength gains.)

The take home message from the above segment, and from many other reports, is simple. Data strongly suggest that our exercise programs should include both aerobic and resistance training.

A Confession, and a Request

See what I mean about details in the segment above? I’ve gone through hundreds of similar scientific articles as background to write this piece, and the science is rock solid. Maybe that’s why more information hasn’t appeared in the popular press. It’s not easy to summarize everything that is known about these magical molecules in one single article. Here’s my confession: I offered a version of this piece to three large newspapers, two in New York and one in Washington, D.C., and I struck out. Zero for three. Didn’t hear a word of response. So I’m printing it here.

And now that request: If you think this information regarding the importance of exercise in maintaining health is important, would you please alert others to this post? Please share this post with others and introduce them to exerkines: the magical molecules of exercise. This information likely will stimulate them to increase their physical activity. Everyone I’ve shown drafts of this article suddenly became eager to exercise more. I’ve written a bit about exercise here earlier (see here, and here ), and I plan to cover more medical topics in the future.

What’s next for exerkines?

For people unable to exercise because of illness, injury, or age, scientists are developing synthetic exerkines to simulate some of exercise’s effects. Several such drugs targeting metabolic disease, inflammation, and muscle loss are already in Phase 2 clinical trials.

So, science is catching up with what our bodies already know. Take a moment to imagine a future in which a pharmaceutical company has produced a capsule containing every exerkine known to be secreted during exercise. Try to guess how much such a miracle pill would cost. Would you buy it?

Or would you just lift some weights and take a brisk walk?