Muscles are an endocrine organ: how they communicate with the rest of the body

Introduction

For a long time, muscles were viewed simply as the body's engine. They contract, move the skeleton, and make it possible to walk, lift, and run. That was all there was to it.

That view has changed. Over the last twenty years, researchers have shown that muscles also function as a gland. When they work, they release signaling molecules that travel through the blood and affect organs throughout the body.

These signaling molecules are called myokines, and their discovery has provided a new explanation for something that has long been a mystery: why physical activity affects so many different aspects of health, from blood sugar to mood.

In this article, we go through what myokines are, how they were discovered, which ones are the most studied, and what this means for how we view exercise.

An old mystery

It has long been known that physical activity is good for your health. But it was difficult to explain why.

Exercise affects blood sugar, fat metabolism, the immune system, mood, and brain function. Many of these effects did not seem to have any direct connection to the movement itself. How could a muscle in the leg affect the liver or the brain?

Researchers long speculated that working muscles must send out some form of signal. They spoke of a hypothetical "work factor," but no one knew what it consisted of.

The discovery in Copenhagen

A breakthrough came from the research group surrounding the Danish physician and researcher Bente Klarlund Pedersen at the University of Copenhagen.

The group studied a signaling molecule called interleukin-6, abbreviated as IL-6. It was already known as part of the immune system and was associated with inflammation.

The researchers discovered that the level of IL-6 in the blood rose sharply during physical activity, in some cases up to a hundredfold. And it was not the immune cells that accounted for the increase; it was the working muscles themselves.

In the mid-2000s, the research group proposed that signaling molecules produced and released by muscle fibers that affect other tissues should be called myokines. This gave birth to a new view of muscles: not just as an engine, but as an organ that produces hormone-like signals.

Hundreds of signaling molecules

Since the discovery of IL-6, the picture has expanded significantly.

Today, skeletal muscle is described as an organ with the ability to produce hundreds of myokines. Not all of them have been mapped, and for many, their function remains unclear. However, some have been studied particularly closely.

IL-6: the paradox

The most studied myokine is also the most confusing.

IL-6 is associated with inflammation. In cases of chronic illness and obesity, levels can be elevated for long periods, which is linked to poorer health.

However, when IL-6 is released from working muscles during exercise, the picture is different. Levels rise sharply but briefly, and research has shown that IL-6 from muscles can then help trigger the release of other signaling substances that act to dampen inflammation.

IL-6 from muscles is also involved in the body's energy metabolism during exercise, for example by influencing how fat and sugar are used.

The difference, therefore, lies in the context. The same signaling substance can have different effects depending on whether it is released in short pulses during exercise or remains chronically elevated.

Muscles and mood

One of the most notable studies in this field came from researchers at Karolinska Institutet and was published in the scientific journal Cell in 2014.

It concerns a substance called kynurenine. It is formed in the body and can enter the brain, where high levels have been linked to depression during stress.

The researchers showed that trained muscles in mice produced more of an enzyme that converts kynurenine into another substance, kynurenic acid. Kynurenic acid cannot pass into the brain.

The muscles thus acted as a kind of filter. Mice with this ability in their muscles were more resistant to stress-induced depression-like behaviors, and mice that lacked it were more vulnerable.

These are animal studies, and a later study on humans with depression did not find any lasting change in blood kynurenine levels after twelve weeks of exercise. The mechanism is therefore not confirmed in humans. However, the study provided a possible biological explanation for how muscles could influence the brain.

Muscles and memory

Another notable study was published in Cell Metabolism in 2016.

The researchers looked for substances secreted by muscles and found an enzyme called cathepsin B. In mice, levels rose in both muscles and blood when they ran.

Mice that lacked cathepsin B did not experience the same improvement in memory or the same formation of new nerve cells in the hippocampus from running as other mice.

Levels of cathepsin B also rose with exercise in monkeys and humans. In humans, the levels were linked to fitness and performance on memory tests.

The human results are correlations from a small study, and it is still not fully clear what role cathepsin B from muscles plays. But the study is one of the clearest examples of how researchers are trying to connect muscles and the brain.

Irisin: the hormone that sparked debate

In 2012, a study was published in Nature describing a new myokine that was named irisin, after the Greek messenger goddess Iris.

The study attracted a great deal of attention because, in animal experiments, irisin appeared to be able to make white adipose tissue behave more like brown adipose tissue, which consumes energy to generate heat. It was interpreted by many as a potential exercise hormone.

Then came the objections. In 2015, researchers showed that the commercial methods used to measure irisin in the blood were not reliable, as the antibodies reacted to other proteins. This raised the question of whether irisin existed at all in measurable amounts in humans.

That same year, the original research group published a study in which they used a different method, mass spectrometry, and were able to detect irisin in human blood, albeit in low levels.

The debate is not entirely settled. Irisin is a current example of how an exciting discovery may require years of scrutiny before it stands on firm ground.

Muscles and blood sugar

This is perhaps the most important part for everyday health, and it is well-established.

Muscles are the body's primary recipient of sugar when insulin signals that blood sugar should be lowered. When muscles do not respond well to insulin—a condition known as insulin resistance—the risk of type 2 diabetes increases.

But muscles have a second pathway. When they work, they can take up sugar from the blood even without insulin. The work itself causes sugar transporters to move to the cell surface.

That pathway also works in people with insulin resistance. This is one of the reasons why physical activity is so effective for blood sugar, and why even a short walk after a meal can make a difference.

The muscle as a brake

Not all myokines promote growth.

An early discovered signaling substance from the muscles is called myostatin. Its job is to limit muscle growth. Animals that lack functional myostatin develop significantly larger muscles than normal.

This shows that muscles do not just send signals to other organs, but also regulate themselves.

What does this mean for you?

Research on myokines is still in its infancy, and many findings come from animal studies. However, some conclusions can be drawn.

1. Muscles need to work to send signals. Myokines are released when muscles contract. It is the movement that triggers the system.

2. Both strength and endurance count. Different types of exercise affect different signaling pathways. Combining them provides the broadest effect.

3. Muscle mass is an asset throughout life. More muscle means a larger organ that can take up blood sugar and send signals. This makes strength training particularly important as you age.

4. Even short bursts count. The effect of muscle work on blood sugar is visible after only a short time, which makes short walks and movement breaks valuable.

5. There is no supplement that can replace exercise. Myokines are produced by muscle activity. No pill or powder can trigger the same signaling system.

When should you seek medical care?

Contact your primary care center if you:

• Have unexplained muscle weakness or notice that your muscles are becoming weaker rapidly
• Have muscle pain that does not go away
• Want to start exercising but have heart or lung disease, diabetes, or another chronic condition
• Have elevated blood sugar and want to know how exercise can affect it

Read more at1177 Vårdguiden.

Summary

Muscles are not just the body's engine. They also function as an endocrine organ that releases hundreds of signaling molecules, known as myokines, when they are active.

The discovery began with IL-6 in Copenhagen and has since grown into its own field of research. Myokines have been linked to blood sugar, fat metabolism, inflammation, and, in animal studies, to mood and memory. One of the most talked-about, irisin, demonstrates how important it is that new findings are scrutinized carefully.

The most well-established link is to blood sugar. Working muscles can take up sugar even without insulin, a process that functions even in cases of insulin resistance.

The conclusion is simple. Every time you use your muscles, they send signals to the rest of the body. This is one of the best explanations available for why physical activity affects so much more than just the muscles themselves.

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Sources

• Pedersen BK, Febbraio MA: Muscle as an endocrine organ: focus on muscle-derived interleukin-6 (Physiological Reviews, 2008)
• Pedersen BK: From the discovery of myokines to exercise as medicine (Danish Medical Journal)
• Agudelo LZ et al: Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression (Cell, 2014)
• Twelve-week physical exercise does not have a long-lasting effect on kynurenines in plasma of depressed patients (Neuropsychiatric Disease and Treatment, 2017)
• Moon HY et al: Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function (Cell Metabolism, 2016)
• Boström P et al: A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis (Nature, 2012)
• Jedrychowski MP et al: Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry (Cell Metabolism, 2015)
• Richter EA, Hargreaves M: Exercise, GLUT4, and Skeletal Muscle Glucose Uptake (Physiological Reviews, 2013)
• McPherron AC et al: Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member (Nature, 1997)
• EFSA: Health claims for magnesium, vitamin D and zinc