Myokines are signaling molecules released by skeletal muscle, and they turn every bout of physical activity into something like a pharmacy run for your entire body. The concept dates to the early 2000s, when researchers discovered that contracting muscles secrete proteins that travel through the bloodstream and influence organs as distant as the brain, liver, and bones. Hundreds of these molecules have been catalogued since then, and the picture they paint is striking: muscle is not just a mechanical structure for movement but also one of the largest endocrine organs you have.
How Muscle Became an Endocrine Organ
The story starts with interleukin-6, or IL-6. Scientists noticed that IL-6 levels in the blood can rise as much as 100-fold during prolonged exercise, and that the source was the muscle fibers themselves rather than immune cells.1PubMed. Muscle as an endocrine organ: focus on muscle-derived interleukin-6 That was a surprise. IL-6 had been known mainly as an immune molecule linked to inflammation. Finding that muscles pump it out in massive quantities during a run or a bike ride reframed the whole relationship between exercise and physiology. Researchers proposed the term “myokine” for any cytokine or peptide produced, expressed, and released by muscle fibers that exerts effects on other tissues.1PubMed. Muscle as an endocrine organ: focus on muscle-derived interleukin-6
Since that initial discovery, the myokine family has expanded well beyond IL-6. Irisin, brain-derived neurotrophic factor (BDNF), interleukin-15 (IL-15), myostatin, follistatin, follistatin-like 1, meteorin-like protein (Metrnl), cathepsin B, and many others all qualify. Some promote muscle growth, others talk to fat tissue, and still others cross the blood-brain barrier. The unifying idea is that working muscles broadcast chemical messages that coordinate the body’s response to physical stress.
What Triggers Myokine Release
You might assume that the physical squeezing of muscle fibers during contraction is what pushes myokines into the bloodstream. Lab work on cultured muscle cells tells a more specific story. When researchers electrically stimulated muscle tubes and then blocked the actual contraction using a chemical inhibitor, IL-6 still poured out. But when they chelated calcium ions so that the intracellular calcium surge couldn’t happen, IL-6 secretion stopped completely.2PLoS ONE. Evidence for acute contraction-induced myokine secretion by C2C12 myotubes In other words, it is the calcium wave inside the muscle cell, not the mechanical shortening itself, that flips the switch. This matters because it hints that anything triggering intracellular calcium flux in muscle could theoretically stimulate myokine release, and it helps explain why even very light exercise still produces some signaling.
Metabolic Effects on Fat and Blood Sugar
One of the most studied functions of myokines is their influence on how the body handles fuel. IL-6 released during exercise triggers fat breakdown in adipose tissue, freeing up energy stores for the working muscles.3PubMed Central. Functional role of skeletal muscle-derived interleukin-6 and its effects on lipid metabolism In lab studies using primary human muscle cells, IL-6 boosted fat oxidation roughly two-and-a-half-fold, while also increasing glucose storage and uptake.4Molecular Endocrinology. Signaling Specificity of Interleukin-6 Action on Glucose and Lipid Metabolism in Skeletal Muscle Those two effects appear to run through separate molecular pathways, which suggests that muscle-derived IL-6 fine-tunes both fat burning and sugar handling at the same time.
The liver gets direct instructions, too. During bicycle exercise, muscle-derived IL-6 signals the liver to ramp up glucose output, helping keep blood sugar steady when muscles are guzzling it.5Endocrine Reviews. Muscle–Organ Crosstalk: The Emerging Roles of Myokines This muscle-to-liver communication loop is a clear example of myokines coordinating organs in real time during physical activity. Beyond acute exercise, the broader class of myokines has been explored for its impact on non-alcoholic fatty liver disease, where resistance exercise and the myokines it releases appear to support healthier lipid processing in liver tissue.6PubMed Central. Myokines: Crosstalk and Consequences on Liver Physiopathology
Turning White Fat Into a Calorie Burner
Irisin, identified in 2012, generated enormous excitement because of its ability to convert white fat cells into something resembling brown fat. Brown fat burns calories to generate heat, so the idea that a muscle-derived hormone could flip a switch in ordinary body fat was tantalizing for obesity research. In mice, irisin stimulated white fat cells to express UCP1, the key protein in heat-generating brown fat, and even mildly elevated irisin levels increased energy expenditure without any change in food intake or physical movement.7PubMed Central. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
Follow-up research in human cells confirmed the browning effect. Irisin upregulated browning-associated genes in cultured mature white fat cells and boosted cellular energy metabolism, increasing thermogenesis at concentrations as low as 5 nanomoles per liter.8PubMed. Irisin exerts dual effects on browning and adipogenesis of human white adipocytes However, the picture has nuance. Irisin’s browning effect works well on subcutaneous white fat (the kind under your skin) but does not appear to activate UCP1 in visceral fat, the deep belly fat wrapped around organs.9PubMed Central. Effects of irisin on the differentiation and browning of human visceral white adipocytes Visceral fat may still respond to irisin through a different, UCP1-independent pathway, but the potent browning response seems to be location-specific.
Anti-Inflammatory Signaling
Chronic low-grade inflammation underlies many modern diseases, from type 2 diabetes to heart disease to depression. Myokines offer a partial explanation for why regular exercise lowers inflammation throughout the body. When muscles contract, the IL-6 they release follows a pathway entirely different from the IL-6 produced during infections. Exercise-derived IL-6 stimulates the release of anti-inflammatory cytokines like IL-1ra and IL-10, while simultaneously suppressing TNF-alpha, a key promoter of inflammation.10PubMed. The anti-inflammatory effect of exercise The distinction is important: IL-6 from immune cells during illness is part of the inflammatory cascade, but IL-6 from exercising muscle actively pushes the body toward an anti-inflammatory state.
This isn’t limited to IL-6 alone. The broader cocktail of myokines released during exercise mediates both systemic anti-inflammatory effects and more targeted effects on visceral fat, which is itself a source of inflammatory molecules.11PubMed Central. The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases In a sense, working muscles are telling the rest of the body to calm down.
Effects on the Brain
The idea that exercise sharpens thinking has been around for centuries, but myokines provide a molecular explanation. BDNF, the molecule most famous for supporting the growth and survival of neurons, is also produced by contracting skeletal muscle. Among several brain-active myokines, BDNF is the most studied for its role in adult neurogenesis and the strengthening of synaptic connections.12PubMed. Roles of myokines in exercise-induced improvement of neuropsychiatric function
A more indirect route has also been identified. Cathepsin B, a protein secreted from muscles during exercise, travels through the bloodstream and appears to upregulate BDNF production in the brain, and this chain has been linked to improved cognitive function.12PubMed. Roles of myokines in exercise-induced improvement of neuropsychiatric function So the muscle-to-brain connection has at least two lanes: BDNF released directly from muscle, and secondary molecules like cathepsin B that boost brain BDNF production once they arrive. This is one reason that exercise interventions keep showing cognitive benefits in populations ranging from healthy young adults to people with neurodegenerative conditions.
Building Bone and Maintaining the Skeleton
Irisin’s résumé extends beyond fat. Mice treated with a micro-dose of recombinant irisin showed improved cortical bone mass, geometry, and strength, effects that resemble what physical activity does to the load-bearing skeleton.13PubMed. Crosstalk Between Muscle and Bone Via the Muscle-Myokine Irisin This makes intuitive sense: muscle and bone are physically attached, and the skeleton needs signals about the mechanical demands being placed on it. Myokines serve as part of that communication. The implication for conditions like osteoporosis is significant, because it suggests that muscle activity protects bone not just through mechanical loading but also through chemical signaling.
Cardiovascular Protection
The heart and blood vessels benefit from their own set of myokine messages. Follistatin-like 1 (FSTL1), a protein released by exercising muscle, has been shown to have beneficial actions on both cardiac and endothelial function.14PubMed Central. Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury Research in vascular biology has linked FSTL1 to endothelial repair, nitric oxide signaling, and the blood vessel adaptations that come with regular exercise.15PubMed Central. Exercise-induced Myokines and Muscle-Vascular Crosstalk in Peripheral Artery Disease Management: From Bench to Practice Nitric oxide keeps blood vessels flexible and dilated, and any molecule that supports that pathway has implications for blood pressure and vascular health. Researchers are actively investigating whether myokines could serve as predictive biomarkers for cardiovascular disease risk, though more work is needed to determine how well they predict clinical outcomes.16PubMed Central. Circulating Myokines as Novel Biomarkers for Cardiovascular Diseases
Muscle Growth, Muscle Loss, and the Balance Between Them
Not all myokines push the body in the same direction. Myostatin is a powerful brake on muscle growth. It belongs to the same signaling family as several other growth regulators, and its job is to keep muscle mass from growing unchecked. Follistatin counteracts myostatin, and studies from mice to monkeys have demonstrated that increasing follistatin leads to larger, stronger muscles.17PubMed Central. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease Follistatin works both by blocking myostatin and by inhibiting activin, another member of the same signaling family that limits muscle growth. It also drives muscle cell proliferation independently.18PubMed. Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin
This tug-of-war between growth-promoting and growth-limiting myokines becomes especially relevant with aging. As people get older, the balance shifts. Protective myokines like IL-15 and IGF-1 decline, while myostatin and activin A increase. The result is a progressive loss of muscle mass and function, and the disruption shows up in protein metabolism, mitochondrial performance, and chronic inflammation within the muscle itself.19PubMed Central. The role and mechanisms of myokines in sarcopenia: new intervention strategies for the challenges of aging Another age-related myokine, Dkk3, rises in both skeletal muscle and the bloodstream in sarcopenia patients. Overexpressing Dkk3 in young mice recreates the muscle wasting seen in old animals, while reducing it in old mice improves muscle mass and strength.20Translational Medicine of Aging. The functions of sarcopenia related myokines Identifying which myokines go wrong during aging opens the door to targeted interventions, and Dkk3 in particular has been flagged as a potential drug target.
Myokine Disruption in Obesity and Diabetes
The myokine profile changes not only with age but also with metabolic disease. In people with obesity, circulating myostatin levels rise, which may worsen the metabolic decline in muscle that eventually contributes to type 2 diabetes. Meanwhile, circulating irisin levels drop in people with type 2 diabetes, and exercise can bring them back up. Meteorin-like protein (Metrnl), another myokine, runs lower in people with obesity and diabetes, and higher circulating Metrnl levels have been associated with reduced risk of type 2 diabetes.21PubMed Central. Myokines: metabolic regulation in obesity and type 2 diabetes The pattern suggests a vicious cycle: metabolic disease blunts the beneficial myokine signals, and the loss of those signals further worsens the disease. Exercise breaks the cycle partly by restoring healthier myokine secretion.
Does the Type of Exercise Matter?
Both aerobic exercise (like running or cycling) and resistance exercise (like weight training) change myokine levels, and a systematic review with meta-analysis found no significant overall difference between the two training modes in their effect on myokines.22PubMed Central. Exercise training mode effects on myokine expression in healthy adults: A systematic review with meta-analysis That said, the magnitude of change varies by specific myokine. An endurance session might drive a bigger spike in IL-6, while resistance training may have a stronger effect on myostatin and follistatin. For most people, the practical takeaway is that any form of regular exercise stimulates myokine release, and the best exercise for myokine benefits is the kind you actually do consistently.
Muscles Talking to Tumors
One of the more surprising directions in myokine research involves cancer biology. Circulating myokines can modulate the tumor microenvironment, essentially delivering signals from muscle directly to the neighborhood around a growing tumor.23PubMed Central. The role of myokines in cancer: crosstalk between skeletal muscle and tumor This is early-stage research, and no one is claiming that exercise cures cancer via myokines. But the finding that muscles can chemically influence tumor behavior adds a layer of biological plausibility to the epidemiological observation that physically active people have lower rates of certain cancers. The mechanisms are still being untangled, and the field is a long way from any clinical application, but the concept of muscle-to-tumor signaling is generating serious interest.
Nutrition and Myokine Levels
What you eat also appears to influence which myokines your muscles release. A study of endurance runners found that carbohydrate intake mattered: runners consuming adequate carbohydrate (above 5 grams per kilogram of body weight per day) had higher levels of myostatin and musclin after a race, while those eating less than 45% of their energy from carbohydrate had lower levels of IL-15 and BDNF. Higher cholesterol intake was associated with lower irisin and apelin, while low fiber intake tracked with lower irisin and BDNF.24PubMed Central. Chronic Low or High Nutrient Intake and Myokine Levels This is a single study in runners, so the findings shouldn’t be taken as dietary prescriptions. But they suggest that fueling your body well may amplify the myokine benefits of exercise, and that poor nutrition could blunt them.
Exercise-Induced Skin Rejuvenation
Myokine signaling reaches organs you might not expect, including the skin. IL-15, a myokine released during endurance exercise, has been shown to attenuate age-associated skin changes in both humans and mice. In this research, exercise-stimulated IL-15 acted as a regulator of mitochondrial function in aging skin, supporting the energy metabolism that keeps skin cells healthier as they age.25PubMed Central. Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging The finding gives a molecular explanation for something exercisers often notice anecdotally: that their skin looks better when they are active.
Where the Science Is Heading
The therapeutic potential of myokines has attracted significant attention, but the field is still working through basic questions. Researchers are investigating whether specific myokines, or drugs that mimic their effects, could treat conditions like sarcopenia, obesity, and cardiovascular disease. Several myokine pathways look promising, but the literature shows substantial variation in the strength of the causal evidence, how well the receptors and targets are understood, and how close any of these approaches are to clinical use.26PubMed Central. Exercise-induced myokines in metabolic regulation: mechanisms, mimetics, and translational potential The idea of an “exercise pill” that replicates myokine signaling without actual physical activity is a recurring headline, but for now, no synthetic approach captures the full scope of what contracting muscles release. Some candidates, like myostatin inhibitors for muscle wasting, have entered clinical trials, though their success has been mixed. Others, like Metrnl and decorin, are still being characterized as potential biomarkers before anyone attempts to use them therapeutically.16PubMed Central. Circulating Myokines as Novel Biomarkers for Cardiovascular Diseases The gap between discovering a myokine and turning it into a treatment is wide, but the pace of discovery has been fast enough that the field looks genuinely different from where it stood even a decade ago.