Myokines: Connecting Movement, Muscles and Well-Being

KineSophy explores connections between physical fitness and movement and non-physical qualities like intelligence, resilience and overall well-being. Some of these connections are observational—for example, exposing oneself to physical challenges makes a person better equipped to face non-physical challenges. Others are based on scientific research, such as the strong connection between exercise and cognitive performance. But it turns out that there is a biological factor underpinning the many benefits of physical movement: a class of molecules called myokines.

The Discovery of Myokines

In 1999, a research team led by the Danish physiologist Bente Klarlund Pedersen published a paper describing a protein called interleukin-6 (IL-6). In a study of marathon runners, the researchers found that blood levels of IL-6 were one hundred times higher at the end of the race than at the start.

Intrigued, Pedersen attached weights to the ankles of six seated men. He placed IVs in each of the men’s legs to draw blood and had them slowly kick one leg while keeping the other leg motionless. Over the course of the experiment, IL-6 levels increased in each man’s kicking leg, but not in their stationary legs. Pedersen concluded that the muscles were making IL-6 during movement and secreting it into the bloodstream. It was the first discovery of a class of biological molecules called myokines.

Diagram of the action of myokines from muscles to other organs

The Muscle-Endocrine System

Myokines are small proteins that are synthesized in myocytes (muscle cells) and released into the bloodstream in response to muscular contractions. This mechanism allows muscles to act as an endocrine organ, making it part of an anatomical messenger system usually limited to the hypothalamus, thyroid gland, adrenal glands and the hormones they control. Myokines can exert their effects in the muscle itself or on a variety of tissues and organs, including adipose tissue, bone, the liver, the brain, the gut, the pancreas, the vascular bed and skin. As a result, myokines influence cognitive performance, lipid and glucose metabolism, browning of white fat, bone formation, muscle growth, skin structure, inflammation and tumor growth.

Scientists have now reported over 3,000 different myokines, including more than 600 in humans. As of 2020, scientists only know the biological function of about 5% of all known myokines. But the identification of these molecules has opened the door to a new understanding of the importance of movement.

Here are some better-known myokines and their effects:


Over twenty years after its discovery, IL-6 remains the most-studied myokine. Research has shown that IL-6 helps reduce abdominal fat and induces browning of white adipose tissue (fat). High levels of abdominal fat—especially white abdominal fat—increase the risk of heart disease, type 2 diabetes, dementia, colon cancer and breast cancer. In contrast, brown fat improves metabolism. Consequently, scientists are working to better understand how to use brown fat activity to treat obesity, diabetes and other metabolic disorders.

Additionally, IL-6 enhances insulin-stimulated glucose uptake and fat oxidation and helps control glucose levels following meals. As such, IL-6 may be an important factor in preventing diabetes and obesity. Research has also shown that IL-6 has anti-inflammatory effects, boosts the effects of the immune system’s natural killer cells and controls tumor growth.

Interleukin-15 (IL-15)

IL-15 accumulates in muscles in response to regular exercise and is involved in slowing skin aging.


Irisin is secreted from skeletal muscle after physical exercise. It was first reported as a potential mediator of the beneficial effects of exercise. It is also known to induce skeletal muscle hypertrophy (growth) and has beneficial effects on cognitive function. Additionally, irisin has been shown to brown white adipose tissue in mice.

Secreted Protein Acidic and Rich in Cysteine (SPARC)

Exercise-stimulated SPARC helps destroy colon cancer cells. It may also help repair muscle damage.

Oncostatin M

Oncostatin M combines with irisin to shrink breast cancer tumors and with SPARC to suppress colon cancer growth.

Brain-Derived Neurotrophic Factor (BDNF)

BDNF produced by the muscles helps regenerate muscle tissue after injury. And as its name suggests, this myokine also acts on the brain, where it decreases appetite and increases the creation of new nerves in the hippocampus. As a result, BDNF assists with the exercise-induced improvement of cognitive functions like memory and learning.

Child running into the sun

Cathepsin B (CTSB)

CTSB assists with the brain-boosting benefits of BDNF, including brain cell survival and learning.


This myokine helps increase muscle mass by increasing protein synthesis and inhibiting protein degradation. It is especially prevalent in slow-twitch muscle fibers in comparison to fast-twitch fibers.


Like myonectin, decorin is also secreted during skeletal muscle contraction and plays an important role in muscle growth.

Fibroblast Growth Factor 21 (FGF21)

FGF21 also plays a role in skeletal muscle hypertrophy. But perhaps more importantly, it protects against the aging of blood vessels in the brain.

Follistatin-like 1 (FSTL1)

FSTL1 is produced by both skeletal and cardiac muscle cells. Research shows that FSTL1 also protects the cardiovascular system by improving the function of the cells lining the heart and blood vessels and facilitating blood flow.

Myokines and Well-Being

Though research on myokines is still in its infancy, it is clear that these molecules facilitate important connections between movement and total well-being. Myokines explain many of the phenomena examined on KineSophy, from the physical benefits of exercise to the link between movement and cognitive and psychological health.

We have known for centuries that physical movement is an important part of a happy, healthy, fulfilled life. Understanding the role of myokines offers insights into the mechanism behind these deep connections at the heart of what makes us human.


  1. DeSilva, Jeremy. First Steps: How Upright Walking Made Us Human. HarperCollins, 2021.
  2. Hojman, Pernille et al. “Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment.” Cell Metabolism, 27(1), 2018.
  3. Lee, Jong Han and Jun, Hee-Sook. “Role of Myokines in Regulating Skeletal Muscle Mass and Function.” Frontiers in Physiology, 2019.
  4. Pedersen, Line et al. “Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution.” Cell Metabolism, 23(3), 2016.
  5. Piccirillo, Rosanna. “Exercise-Induced Myokines With Therapeutic Potential for Muscle Wasting.” Frontiers in Physiology, 2019.
  6. Severinsen, Mai Charlotte Krogh and Pedersen, Bente Klarlund. “Muscle–Organ Crosstalk: The Emerging Roles of Myokines.” Endocrine Reviews, 41(4), 2020.
  7. Wein, Harrison. “How brown fat improves metabolism.” NIH Research Matters, 2019.
  8. Zhe-Cheng, Jiang et al. “Myokine: a novel target for exercise to improve cognitive function?” British Journal of Sports Medicine, 52(12), 2018.