Introduction

Regular physical activity stands as one of the most effective interventions for preventing and managing chronic disease. Exercise improves cardiovascular function, increases muscle strength, supports mental well-being, and reduces the risk of type 2 diabetes, obesity, cardiovascular disorders, and certain cancers. Over the past two decades, researchers have uncovered a key mechanism underlying these benefits: the release of myokines—a class of signaling proteins secreted by skeletal muscle fibers during contraction. These molecules act as endocrine and paracrine messengers, coordinating systemic metabolic adaptations and orchestrating cross-talk between muscle, liver, adipose tissue, brain, and the immune system. Understanding how exercise-induced myokines influence systemic metabolism and overall health provides a molecular framework for optimizing exercise prescriptions and developing novel therapeutic strategies for individuals who cannot exercise.

The global burden of physical inactivity is staggering. The World Health Organization estimates that insufficient physical activity contributes to over 3 million preventable deaths annually. Sedentary lifestyles drive insulin resistance, dyslipidemia, chronic inflammation, and metabolic dysfunction. Exercise counteracts these effects through multiple mechanisms, but the discovery of myokines has revealed that skeletal muscle itself is an active endocrine organ. When muscles contract, they release these signaling molecules into the bloodstream, directly communicating with distant tissues. This paradigm shift—from viewing muscle as a passive executor of movement to recognizing it as a central regulator of whole-body metabolism—has opened new avenues for understanding how exercise protects health and for developing exercise-mimetic therapies.

The Biology of Myokines

Myokines belong to the cytokine and peptide family and are synthesized and released by skeletal muscle cells in response to mechanical, metabolic, or inflammatory stimuli. The term "myokine" (from Greek myo meaning muscle and kinos meaning movement) was first proposed by Dr. Bente Klarlund Pedersen in the early 2000s to describe muscle-derived signaling proteins that mediate the health effects of exercise. Unlike classical hormones produced by dedicated endocrine glands, myokines are produced by the muscle itself and can act locally within the muscle (autocrine/paracrine) or enter the circulation to affect distant organs (endocrine). Their expression and secretion are tightly regulated by exercise duration, intensity, and mode, as well as by intracellular energy status and calcium flux pathways.

Myokines exert their effects through binding to specific receptors on target cells, triggering intracellular signaling cascades that modulate gene expression, cellular metabolism, and inflammatory responses. The repertoire of known myokines has expanded significantly, with dozens now identified—including interleukins, growth factors, and novel proteins. The most extensively characterized myokines include IL-6, myonectin, follistatin-like 1 (FSTL1), irisin, brain-derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF), and fibroblast growth factor 21 (FGF21). Each contributes to distinct aspects of metabolism, tissue repair, and systemic health. The emerging concept of the "myokinome" refers to the complete set of myokines secreted by muscle, and mapping this landscape remains an active area of research using proteomics and transcriptomics.

Key Myokines and Their Functions

  • Interleukin-6 (IL-6): Initially classified as a pro-inflammatory cytokine, IL-6 released from contracting muscles has anti-inflammatory and metabolic properties. It stimulates glucose uptake in muscle cells, promotes hepatic gluconeogenesis to maintain blood glucose, enhances lipolysis in adipose tissue, and increases fat oxidation. IL-6 also triggers the release of anti-inflammatory cytokines such as IL-10 and inhibits tumor necrosis factor-alpha (TNF-α) production. The exercise-induced IL-6 response is transient and proportional to exercise duration and intensity, peaking at the end of exercise and declining rapidly during recovery.
  • Myonectin (CTRP15): Secreted by skeletal muscle after exercise, myonectin enhances fatty acid uptake in the liver and adipose tissue, reduces circulating triglycerides, and improves lipid clearance. It also supports mitochondrial biogenesis in muscle cells and suppresses hepatic de novo lipogenesis, protecting against fatty liver disease. Myonectin levels correlate positively with exercise volume and fitness status.
  • Follistatin-like 1 (FSTL1): This myokine improves insulin sensitivity by activating AMP-activated protein kinase (AMPK) and Akt signaling in peripheral tissues. FSTL1 reduces systemic inflammation by inhibiting NF-κB activation in macrophages and endothelial cells. It also promotes endothelial function and angiogenesis, contributing to cardiovascular health. Resistance training appears to be a particularly strong stimulus for FSTL1 release.
  • Irisin: Cleaved from the membrane protein FNDC5, irisin is released during exercise and induces browning of white adipose tissue (WAT), converting energy-storing white adipocytes into energy-expending beige adipocytes. Irisin enhances glucose metabolism, improves mitochondrial function in multiple tissues, and activates PGC-1α in a feedforward loop. Its discovery generated significant interest as a potential therapeutic target for obesity and metabolic disease.
  • Brain-derived neurotrophic factor (BDNF): Produced in muscle and the central nervous system, BDNF supports neuronal survival, synaptic plasticity, and cognitive function. Muscle-derived BDNF contributes to peripheral nerve maintenance and metabolic regulation. Exercise increases BDNF levels in both muscle and brain, linking physical activity to improved mood, learning, and neuroprotection.
  • Leukemia inhibitory factor (LIF): LIF is secreted by contracting muscle and promotes muscle satellite cell proliferation and hypertrophy. It also exerts metabolic effects by enhancing fatty acid oxidation and improving insulin sensitivity. LIF levels rise significantly after resistance exercise and contribute to muscle repair and growth.
  • Fibroblast growth factor 21 (FGF21): While primarily produced in the liver, FGF21 is also secreted by muscle during exercise. It acts as a metabolic regulator, increasing energy expenditure, promoting fat oxidation, and improving insulin sensitivity. FGF21 levels are elevated after prolonged endurance exercise and may play a role in the metabolic adaptation to fasting and exercise stress.

Exercise-Induced Myokine Signaling Pathways

The secretion of myokines is initiated by muscle contraction and the accompanying metabolic stress. Key intracellular sensors such as AMPK, Ca²⁺/calmodulin-dependent protein kinase (CaMK), and p38 MAPK are activated, leading to increased transcription and translation of myokine genes. AMPK acts as a cellular energy sensor, responding to increases in the AMP/ATP ratio that occur during intense exercise. It directly phosphorylates and activates transcription factors that drive myokine expression. CaMK is activated by calcium oscillations during contraction and signals through pathways that converge on PGC-1α and other regulators.

The production of IL-6 is driven by AMPK and by the transcription factor NF-κB, with calcium signaling also contributing. Irisin expression depends on PGC-1α, which is itself upregulated by exercise and coordinates mitochondrial biogenesis alongside myokine production. FSTL1 and myonectin are regulated by AMPK and by mechanical stress pathways that involve integrins and focal adhesion signaling. The magnitude and temporal pattern of myokine release vary with exercise parameters: acute endurance exercise promotes a rapid, transient IL-6 increase that can reach 100-fold above resting levels; resistance training tends to favor myonectin, FSTL1, and LIF responses; and high-intensity interval training produces a robust but brief IL-6 surge with sustained irisin elevation.

Once released into the circulation, myokines interact with specific receptors on target organs. IL-6 binds to the IL-6 receptor and gp130 complex on hepatocytes and adipocytes, activating STAT3 and MAPK signaling. Irisin acts through an unidentified receptor that triggers brown adipose-like thermogenesis and PGC-1α activation. Myonectin engages the adiponectin receptor 1 (AdipoR1) in liver cells, activating AMPK and PPARα pathways. FSTL1 binds to membrane receptors that activate AMPK and Akt while inhibiting NF-κB. These signaling events coordinate substrate utilization, insulin action, and energy balance across the body.

Impact on Systemic Metabolism

Exercise-induced myokines exert profound effects on whole-body metabolism by enhancing glucose homeostasis, promoting lipid oxidation, increasing energy expenditure, and reducing chronic low-grade inflammation. These actions are central to the prevention and management of metabolic syndrome, type 2 diabetes, and obesity. The metabolic effects are both acute—occurring during and immediately after exercise—and chronic, resulting from repeated exercise bouts that improve baseline metabolic function.

Glucose Regulation

IL-6 is a primary regulator of exercise-induced glucose metabolism. During physical activity, IL-6 stimulates glucose uptake via AMPK-mediated translocation of GLUT4 to the muscle cell membrane, independent of insulin. This effect improves postprandial glucose clearance and reduces reliance on insulin, which is particularly beneficial for individuals with insulin resistance. In the liver, IL-6 enhances gluconeogenesis to maintain blood glucose availability for the working muscle, preventing hypoglycemia during prolonged exercise. Over time, regular exercise-induced IL-6 secretion improves insulin sensitivity in skeletal muscle, adipose tissue, and liver, thereby lowering fasting glucose and HbA1c levels. Irisin also contributes to glycemic control by promoting glucose uptake in muscle and by inducing beige adipocyte formation, which increases glucose utilization. FSTL1 improves insulin signaling through Akt activation, further enhancing glucose disposal.

Lipid Metabolism

Myonectin and irisin are key mediators of exercise-fueled lipid clearance. Myonectin reduces circulating free fatty acids and triglycerides by enhancing fatty acid uptake in hepatocytes and adipocytes. It also suppresses de novo lipogenesis in the liver, preventing steatosis and protecting against non-alcoholic fatty liver disease. Irisin drives the browning of white adipose tissue, increasing thermogenesis and fat oxidation. Both myokines work in concert with IL-6 to promote lipolysis in adipose stores, mobilizing fatty acids as fuel during and after exercise. The net effect is a reduction in visceral adiposity, improved plasma lipid profiles, and protection against lipotoxicity in peripheral organs. LIF and FGF21 further support lipid oxidation by activating PPARα and increasing mitochondrial fatty acid uptake.

Mitochondrial Function

PGC-1α, a master regulator of mitochondrial biogenesis, is upregulated by exercise and stimulates irisin production. Irisin, in turn, activates PGC-1α in adipocytes and muscle cells, creating a feedforward loop that enhances mitochondrial density and oxidative capacity. FSTL1 and myonectin activate AMPK, which promotes mitochondrial fission, fusion, and quality control through mitophagy. Improved mitochondrial function increases aerobic capacity, supports efficient energy production, and reduces oxidative stress—a hallmark of metabolically healthy tissues. IL-6 also contributes to mitochondrial adaptation by activating AMPK and promoting the expression of mitochondrial genes. The coordinated action of these myokines ensures that muscle and other tissues can meet the energy demands of exercise while building metabolic resilience.

Energy Expenditure and Thermogenesis

Irisin-mediated browning of white adipose tissue is a significant contributor to exercise-induced energy expenditure. Beige adipocytes express uncoupling protein 1 (UCP1), which dissipates the mitochondrial proton gradient as heat rather than producing ATP. This process increases energy expenditure and can counteract weight gain. FGF21 also promotes thermogenesis by activating the sympathetic nervous system and increasing UCP1 expression in brown adipose tissue. The combination of myokine-driven thermogenesis, increased fat oxidation, and improved mitochondrial efficiency creates a metabolic environment that favors energy expenditure over storage, supporting weight management and metabolic health.

Anti-inflammatory and Immunomodulatory Effects

Chronic low-grade inflammation is a central driver of insulin resistance, atherosclerosis, and many age-related diseases. Exercise-induced myokines counter this by establishing an anti-inflammatory milieu. IL-6 released during exercise suppresses the production of pro-inflammatory cytokines such as TNF-α and IL-1β, while stimulating anti-inflammatory mediators including IL-10 and IL-1 receptor antagonist (IL-1ra). This shift reduces systemic inflammation markers like C-reactive protein (CRP) and creates a protected environment for metabolic tissues.

FSTL1 attenuates inflammatory signaling by inhibiting NF-κB activation in macrophages and endothelial cells. It also reduces adhesion molecule expression, limiting leukocyte infiltration into tissues. Myonectin suppresses inflammatory responses in macrophages by promoting an M2 anti-inflammatory phenotype. The cumulative anti-inflammatory effect of myokine action is a key mechanism through which physical activity reduces the risk of metabolic syndrome, type 2 diabetes, and cardiovascular disease. Regular exercisers show lower baseline levels of inflammatory markers, reflecting a sustained anti-inflammatory state that protects against chronic disease.

Myokines in Organ Crosstalk

Myokines serve as the molecular language through which muscle communicates with distant organs. This interorgan communication is central to the systemic benefits of exercise.

Muscle-Liver Axis

IL-6 from contracting muscle signals to the liver to increase gluconeogenesis during exercise, maintaining blood glucose. Myonectin enhances hepatic fatty acid uptake and suppresses lipogenesis, protecting against fatty liver. FGF21 from muscle and liver coordinates metabolic adaptation to exercise and fasting. This axis ensures that the liver supports muscle energy demands while maintaining metabolic health.

Muscle-Adipose Axis

Irisin and IL-6 communicate with adipose tissue to promote lipolysis, browning, and fat oxidation. Myonectin enhances fatty acid uptake in adipocytes, improving lipid clearance. This cross-talk reduces visceral adiposity and improves adipose tissue function, lowering the risk of obesity-related metabolic complications.

Muscle-Brain Axis

BDNF produced in muscle enters the circulation and supports neuronal survival and synaptic plasticity. Exercise-induced BDNF improves cognitive function, mood, and neuroprotection. IL-6 also crosses the blood-brain barrier to influence hypothalamic function and energy regulation. This axis links physical activity to mental health and cognitive preservation.

Muscle-Immune Axis

IL-6 and FSTL1 modulate immune function by promoting anti-inflammatory cytokine profiles and reducing pro-inflammatory signaling. This cross-talk protects against chronic inflammation and may reduce the risk of autoimmune flares. Regular exercise through myokine signaling creates a resilient immune system that responds appropriately to challenges without excessive inflammation.

Clinical Implications and Disease Prevention

The systemic benefits of myokines extend to numerous clinical domains. In insulin resistance and type 2 diabetes, exercise-induced IL-6, irisin, and FSTL1 work together to improve glycemic control, reduce insulin requirements, and lower inflammation. Clinical studies show that individuals who exercise regularly have higher irisin levels and better insulin sensitivity. Obese individuals show altered myokine profiles—often depressed irisin and elevated basal IL-6—that regular exercise can normalize, restoring a healthier metabolic state.

Myokines protect cardiovascular health through multiple mechanisms. FSTL1 improves endothelial function and promotes angiogenesis, enhancing blood flow and tissue perfusion. IL-6 reduces atherosclerotic plaque progression and stabilizes existing plaques by modulating inflammatory cell activity. Irisin and myonectin improve lipid profiles and reduce visceral adiposity, addressing major cardiovascular risk factors. Together, these effects contribute to the well-documented reduction in cardiovascular events among physically active individuals.

Emerging evidence suggests myokines support neurogenesis and cognitive function. BDNF is central to this effect, with exercise-induced BDNF increases linked to improved memory, executive function, and mood. Higher BDNF levels are associated with reduced risk of Alzheimer's disease and other neurodegenerative conditions. The muscle-brain axis mediated by BDNF and other myokines offers a protective pathway against age-related cognitive decline.

Cancer cachexia and sarcopenia—conditions characterized by muscle wasting—may be mitigated by myokine-mediated muscle preservation and metabolic support. LIF promotes muscle satellite cell proliferation and hypertrophy, while IL-6 supports metabolic function in wasting states. Exercise interventions that stimulate favorable myokine profiles are being explored as adjunctive therapies for cancer patients and older adults at risk of sarcopenia.

Given their broad yet specific roles, myokines represent promising therapeutic targets. Researchers are exploring recombinant myokine proteins or small-molecule agonists that mimic exercise effects. However, exercise itself remains the most effective, safe, and accessible way to stimulate a favorable myokine response. The challenge lies in translating this knowledge into practical interventions for individuals who cannot exercise due to injury, disability, or chronic illness.

Exercise Prescription and Myokine Response

Not all exercise produces the same myokine profile, and understanding these differences allows for targeted exercise prescriptions. Endurance exercise (running, cycling, swimming) strongly elevates IL-6 and irisin, with peak levels occurring 30–60 minutes after onset and declining rapidly during recovery. The magnitude of the IL-6 response correlates with exercise duration and the amount of muscle mass engaged. Resistance training (weight lifting) predominantly increases myonectin, FSTL1, and LIF, which support muscle hypertrophy and metabolic repair. The mechanical stress of resistance exercise activates distinct signaling pathways that favor these myokines.

High-intensity interval training (HIIT) produces a robust but brief IL-6 surge and sustained irisin elevation, making it highly effective for metabolic adaptations despite shorter session durations. HIIT also stimulates FGF21 release, linking intense effort with metabolic flexibility. The combination of aerobic and resistance training in a single session appears to produce a complementary myokine response, with IL-6 from the aerobic component and FSTL1/myonectin from the resistance component acting synergistically.

The frequency, intensity, and duration of exercise modulate myokine secretion. Moderate-to-vigorous intensity for 45–60 minutes, performed 3–5 times per week, appears optimal for balancing IL-6, irisin, and myonectin profiles. However, even shorter sessions of 20–30 minutes produce measurable myokine responses, particularly at higher intensities. Individual factors such as age, sex, fitness level, and nutritional status influence responsiveness. Older adults may have blunted myokine responses, making higher volume or intensity necessary to achieve similar effects. Women show different myokine profiles than men, potentially related to hormonal influences on muscle metabolism. Therefore, personalized exercise programs—varying type, volume, and progression—can maximize myokine-driven health outcomes.

Future Research Directions

Current research aims to map the complete myokinome—the full set of myokines—and decipher their tissue-specific signaling networks. Advances in proteomics and high-throughput sequencing are identifying novel myokines at an accelerating pace. Each newly discovered myokine requires characterization of its receptor, signaling pathways, and physiological functions. Preclinical studies are evaluating myokine-based therapies for metabolic disorders, muscle wasting, and inflammatory diseases, with several candidates entering early-phase clinical trials.

Key questions remain: How do myokine functions change with aging or disease? Can combined exercise modes synergize myokine effects? What are the long-term consequences of chronically altered myokine levels? Are there sex-specific differences in myokine responses that require tailored exercise recommendations? Leveraging advances in proteomics, single-cell sequencing, and metabolomics will provide deeper mechanistic insights and facilitate the development of exercise mimetics for individuals unable to exercise.

Myokines are also being evaluated as biomarkers of exercise adherence and metabolic health. Circulating levels of irisin, IL-6, or FSTL1 could gauge an individual's physiological response to training, enabling tailored adjustments to exercise prescriptions. Wearable technology combined with biomarker monitoring could provide real-time feedback on myokine responses, optimizing training loads and recovery periods. Emerging work explores myokine-mediated communication between muscle and gut microbiota, revealing that exercise-induced changes in the microbiome may be partially mediated by myokine signaling. This gut-muscle axis represents a new frontier in understanding how exercise benefits systemic health.

Conclusion

Exercise-induced myokines are integral to the profound health benefits of physical activity. They regulate glucose and lipid metabolism, enhance mitochondrial function, increase energy expenditure, reduce inflammation, and influence brain and cardiovascular health. By understanding the molecular pathways that myokines activate, researchers and clinicians can refine exercise recommendations and develop targeted interventions for metabolic diseases. The evidence is clear: regular, varied physical activity optimizes myokine profiles, supporting systemic metabolism and long-term health.

Incorporating aerobic, resistance, and interval training into weekly routines harnesses these molecular messengers, empowering individuals to take charge of their metabolic health. Even modest increases in physical activity produce measurable improvements in myokine profiles, meaning that any movement is better than none. For those unable to exercise, myokine-based therapies offer hope, though they cannot fully replicate the coordinated, multi-organ response generated by voluntary physical activity. The discovery of myokines has transformed our understanding of exercise as medicine, revealing that every muscle contraction sends a signal of health throughout the body.

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