Myokines: Muscles as an Endocrine Organ

What are myokines and how were they discovered?

Until the early 2000s, skeletal muscles were viewed exclusively as mechanical structures converting chemical energy into movement. In 2000, Bente Pedersen and colleagues (Copenhagen Muscle Research Centre) discovered that plasma IL-6 rises sharply during intense aerobic exercise and that the source of this IL-6 is the contracting muscles themselves. This discovery showed that muscle is not just a motor but a secretory organ.

The term "myokine" was introduced by Pedersen and Febbraio to denote proteins secreted by myocytes in response to contraction. Subsequent proteomic analysis identified hundreds of candidate myokines. A physiologically significant role has been established for several dozen of them; the most studied are IL-6, irisin, BDNF, IL-15, IL-10, IL-1ra, myostatin, fibroblast growth factor 21 (FGF-21), and meteorin-like protein (Metrnl).

How does exercise-induced IL-6 differ from inflammatory IL-6?

IL-6 is the central paradox of myokine physiology. In the context of chronic inflammation and obesity it acts as a pro-inflammatory cytokine. However, muscular IL-6 released during exercise works in a fundamentally different way.

During aerobic work, IL-6 from muscles performs metabolic functions: it stimulates glucose uptake and lipolysis, supporting energy supply during prolonged exercise. At the same time it initiates a chain of anti-inflammatory reactions — suppressing TNF-α and inducing synthesis of IL-10 and IL-1ra. This explains the anti-inflammatory effect of regular aerobic training, despite IL-6 traditionally being associated with inflammation.

The meta-analysis by Ringleb et al. (FASEB Journal, 2026) included 148 studies with 294 exercise protocols and 3622 participants. The effect size for IL-6 was g=1.20 (p<0.001) — the largest among all myokines studied. For IL-10 — g=0.65, for IL-8 — g=0.77, for IL-1ra — g=0.44, for TNF-α — g=0.50 (all p<0.001).

Irisin: the bridge between muscles and the brain

Irisin is a myokine formed by proteolytic cleavage of the membrane protein FNDC5. It is secreted in response to activation of PGC-1α — the master regulator of mitochondrial biogenesis, sensitive to aerobic exercise.

Irisin acts on several target organs:

• Adipose tissue: induces "browning" of white fat — increases expression of the uncoupling protein UCP1, enhancing thermogenesis and energy expenditure.
• Brain: crosses the blood-brain barrier and stimulates BDNF (Brain-Derived Neurotrophic Factor) synthesis in the hippocampus. BDNF is critical for neurogenesis, synaptic plasticity, and memory consolidation.
• Bone: several studies show an anabolic effect of irisin on osteoblasts, although the evidence base in humans remains limited.

BDNF is in turn also directly secreted by contracting muscles. Review PMC12249830 (2025) classifies BDNF as a "metabolic biomarker and potential therapeutic target" with increased concentrations after physical exercise.

What else do myokines do: IL-15 and myostatin

IL-15 is a myokine with a dual anabolic and anti-inflammatory profile. It promotes reduction of visceral fat and improved glucose uptake partly through an insulin-independent pathway. In the meta-analysis by Ringleb et al. (2026), IL-15 showed a significant, albeit moderate, effect (g=0.37, p<0.010) in 12 effect sizes from the study pool.

Myostatin (GDF-8) is an inhibitory regulator of muscle growth: its level decreases during exercise, potentially lifting constraints on hypertrophy. Genetic or pharmacological blockade of myostatin in animal experiments leads to marked increases in muscle mass. In humans the patterns are more complex and less predictable.

Which workouts produce the greatest myokine response?

Ringleb et al. (2026) conducted moderator analysis and established that exercise duration, intensity, and training status significantly moderate the myokine response. Longer and more intense exercise predictably produces a more pronounced signal. Trained athletes and untrained participants differ in their release profile — adaptation to exercise changes the baseline and peak level of several myokines.

Crucially, the authors note that aerobic exercise is a "key component of treatment for a wide range of diseases" precisely through myokine mechanisms. This means the benefits of training extend far beyond the muscular system and are realized through systemic signaling that cannot be replicated by medications.