Understanding exerkines, myokines, muscle–brain communication, immune regulation, and the remarkable systemic effects of muscular activity.
Introduction: Skeletal Muscle Is More Than a Mechanical System
Skeletal muscle is often understood primarily through its mechanical functions.
Muscles generate force, produce movement, stabilize joints, and allow us to interact with the physical environment.
However, contemporary research demonstrates that skeletal muscle is also a metabolically and endocrinologically active tissue.
When muscles contract, they do more than consume energy.
They participate in molecular communication with distant organs.
Muscular activity can influence circulating signaling molecules, immune-cell behavior, glucose metabolism, and neural function.
These discoveries have fundamentally expanded our understanding of exercise physiology.
In 2022, Chow and colleagues published Exerkines in Health, Resilience and Disease in Nature Reviews Endocrinology.
The review examined a growing class of exercise-associated signaling molecules collectively known as exerkines.
Two years later, Walzik and colleagues expanded this research by reviewing the molecular mechanisms through which exerkines influence cellular signaling and tissue adaptation.
Additional investigations have examined their relationship with brain function, immune regulation, and cancer biology.
Together, these findings support an important idea:
Muscular contraction is not merely a mechanical action. It is a biological event that produces signals capable of influencing physiological processes throughout the body.
What Are Exerkines?
Exerkines are signaling molecules released in association with acute or chronic exercise that act through local or systemic communication pathways.
They represent a broad group rather than one specific type of hormone.
Some are proteins or peptides.
Others are metabolites, lipids, nucleic acids, or molecules transported in extracellular vesicles.
Different tissues contribute to exerkine production.
Skeletal muscle releases myokines.
Cardiac muscle produces cardiokines.
The liver releases hepatokines.
Adipose tissue produces adipokines.
Neural tissues can contribute neurokines.
The biological effects depend on the source, concentration, receptor interactions, timing, and physiological context.
Importantly, not every molecule altered during exercise has a proven causal role in exercise-related health benefits.
Exerkine research includes well-characterized pathways alongside emerging mechanisms that remain incompletely understood.
Skeletal Muscle as an Endocrine Organ
An endocrine organ releases substances that influence distant tissues. Skeletal muscle meets this functional description because muscle contraction can stimulate the release of biologically active signaling molecules. Some myokines act locally within muscle. Others may enter circulation and influence distant organs.
This allows muscular activity to contribute to whole-body regulation. For example, exercise can alter signaling relevant to glucose availability, inflammatory responses, and metabolic adaptation.
However, the endocrine function of skeletal muscle should not be interpreted as evidence that larger muscles always produce proportionally greater health benefits. The relationship depends on muscular activity, exercise characteristics, tissue function, and other factors.
Both endurance exercise and resistance training can stimulate biologically meaningful signaling. Their effects overlap but are not identical.
Interleukin-6: Why Context Changes Biological Meaning
Interleukin-6 is one of the most extensively studied exercise-associated signaling molecules.
In inflammatory disease, IL-6 is often discussed as a contributor to inflammatory signaling.
However, IL-6 also rises during muscular activity.
The physiological consequences depend partly on its source and the broader signaling environment.
During exercise, skeletal muscle can release IL-6 into circulation.
This response is influenced by exercise duration, intensity, muscle mass involved, and metabolic conditions.
Exercise-associated IL-6 signaling can contribute to metabolic regulation and may stimulate anti-inflammatory pathways.
These can include increased production of IL-1 receptor antagonist and IL-10 under particular conditions.
This illustrates a fundamental lesson of systems biology.
A molecule cannot be classified as universally beneficial or harmful solely by its name.
Its biological effects depend on the circumstances in which it is produced and the pathways it activates.
Exercise Does Not Simply Suppress Inflammation
Exercise is frequently described as anti-inflammatory.
This description captures some important long-term benefits but can be misleading if interpreted too literally.
Acute exercise can temporarily increase circulating immune cells and certain inflammatory mediators.
These responses may be normal components of physiological adaptation.
With regular training, some individuals experience improvements in markers associated with chronic low-grade inflammation.
However, these changes depend on baseline health, training characteristics, adiposity, medications, and other factors.
The objective of exercise is not to eliminate immune activity.
Appropriate immune responses are essential for host defense, tissue repair, and adaptation.
The more useful goal is improved immune regulation and overall physiological health.
Exercise and Immune-Cell Mobilization
The immune system responds rapidly to physical activity.
During exercise, circulating concentrations of certain immune-cell populations may increase.
These include natural killer cells and selected T-cell populations.
The response reflects interactions among hemodynamic changes, catecholamines, tissue signaling, and other physiological processes.
Following exercise, immune-cell distributions may change again as cells traffic between circulation and tissues.
However, these changes should not be interpreted simply as an increase or decrease in total immunity.
A transient rise in circulating immune cells does not automatically demonstrate better protection against every infection or disease.
Exercise-related immune responses involve changes in cell distribution, signaling, and functional activity.
Clinical relevance depends on the outcome being studied.
Exercise and Anticancer Immunity
In 2024, Fiuza-Luces and colleagues published The Effect of Physical Exercise on Anticancer Immunity in Nature Reviews Immunology.
The authors reviewed evidence suggesting that exercise may influence antitumor immune responses.
Animal studies have demonstrated that physical activity can alter tumor-associated immune-cell infiltration under certain experimental conditions.
Natural killer cells and T lymphocytes have attracted particular interest.
Potential mechanisms involve circulating catecholamines, cytokines, and tissue-specific immune signaling.
However, the authors acknowledged that the mechanisms responsible for exercise-related changes in cancer outcomes remain incompletely understood.
Findings from animal tumor models cannot be assumed to apply identically to human cancers.
Furthermore, the immune effects of exercise may vary according to cancer type, disease stage, treatment, and individual health.
Exercise should therefore be integrated into cancer care based on appropriate clinical evidence—not promoted as a replacement for oncology treatment.
A Major Clinical Trial: Exercise After Colon Cancer Treatment
One of the most important recent developments is the CHALLENGE trial, published in The New England Journal of Medicine in 2025.
This randomized phase 3 trial investigated structured exercise following adjuvant chemotherapy among patients with resected colon cancer.
The study included 889 participants.
Patients were assigned to a structured exercise program or a comparison group receiving health-education materials.
At a median follow-up of 7.9 years, the exercise group demonstrated significantly better disease-free survival.
Five-year disease-free survival was 80.3% in the exercise group compared with 73.9% in the comparison group.
The hazard ratio for disease recurrence, new primary cancer, or death was 0.72.
Findings also favored the exercise group for overall survival.
However, musculoskeletal adverse events were more common among participants receiving the structured exercise intervention.
These results demonstrate that exercise can produce clinically important benefits in a carefully defined oncology population.
They do not establish that exercise prevents or treats every cancer.
Nor do they identify one exerkine as the cause of the survival benefit.
The trial supports appropriately supervised exercise as an important component of care for selected patients after colon cancer treatment.
Muscle–Brain Communication
The relationship between physical activity and brain health extends beyond improved blood flow or cardiovascular fitness.
In 2019, Bente Klarlund Pedersen published Physical Activity and Muscle–Brain Crosstalk in Nature Reviews Endocrinology.
The review discussed mechanisms through which muscular activity may influence neural function.
Potential mediators include myokines, hepatokines, metabolites, and other circulating substances.
Several molecules have attracted particular research interest because of their relationships with neurotrophic signaling, inflammation, metabolism, and cognition.
However, most mechanistic evidence comes from experimental studies.
The exact contribution of individual circulating factors to human cognitive improvement remains uncertain.
The emerging concept is that brain health may be influenced through interactions among skeletal muscle, circulating signals, metabolism, and neural activity.
Brain-Derived Neurotrophic Factor and Exercise
Brain-derived neurotrophic factor, commonly abbreviated BDNF, participates in neuronal survival, synaptic plasticity, and aspects of learning and memory.
Its activity is influenced by physiological and developmental context.
Exercise has been associated with changes in BDNF signaling in experimental studies.
Animal research has demonstrated that physical activity can influence hippocampal neuroplasticity and related molecular pathways.
However, circulating BDNF measurements do not directly reveal BDNF activity within particular brain regions.
Likewise, an increase in blood BDNF does not automatically establish improved cognition.
The value of BDNF research lies in identifying possible biological contributors to exercise-related neural adaptation.
Clinically, cognitive and functional outcomes remain more meaningful than an isolated biomarker.
Cathepsin B and Exercise-Related Neural Adaptation
Cathepsin B is a protease involved in several cellular processes.
Research has investigated its possible role as an exercise-associated signaling molecule.
Experimental findings suggest that exercise-related cathepsin B signaling may influence neural pathways associated with hippocampal function.
Some animal studies have connected these processes with neurogenesis and memory.
However, the translation to human neurological care remains incomplete.
There is no established clinical protocol in which measuring cathepsin B guides exercise prescription for cognitive rehabilitation.
The findings are best understood as mechanistic discoveries that may inform future research.
FNDC5, Irisin, and Neurotrophic Signaling
FNDC5 is a protein associated with several exercise-related signaling pathways.
Its cleavage product, commonly referred to as irisin, has attracted interest in metabolic and neurological research.
Experimental studies have investigated whether FNDC5-related signaling influences BDNF expression and neural function.
However, the physiology of circulating irisin in humans remains an area of active investigation.
Questions concerning secretion, measurement, receptor interactions, and biological effects continue to be studied.
These findings should not be interpreted as evidence that an irisin supplement or isolated signaling molecule can reproduce the cognitive benefits of exercise.
The mechanisms are biologically interesting but not yet equivalent to established clinical interventions.
The Kynurenine Pathway and Psychological Health
Tryptophan metabolism produces several biologically active molecules through the kynurenine pathway.
Some metabolites participate in immune and neural signaling.
Exercise can influence aspects of this pathway.
Pedersen's review describes experimental evidence suggesting that muscular adaptation may increase the activity of enzymes involved in converting kynurenine into kynurenic acid.
In certain animal models, these changes were associated with protection against stress-related behavioral effects.
However, translating these findings into human depression treatment requires caution.
Depression is a complex psychiatric condition involving multiple biological, psychological, and social factors.
Exercise can be a beneficial component of mental healthcare for selected patients, but this does not mean that depression is caused by one abnormal kynurenine pathway.
Nor does it establish that measuring kynurenine metabolites is necessary for ordinary exercise prescription.
The Liver, Adipose Tissue, and Other Sources of Exercise Signaling
Skeletal muscle is not the only tissue participating in the systemic effects of exercise.
The liver contributes to glucose regulation, lipid metabolism, and the release of circulating signaling molecules.
Adipose tissue participates in endocrine communication and substrate storage.
Cardiac muscle responds to mechanical and metabolic demands.
These tissues interact continuously.
Exercise may alter the activity or release of certain factors from each organ.
However, the precise contribution of individual molecules remains incompletely characterized.
The MoTrPAC study illustrates the complexity of these responses by showing thousands of molecular changes across multiple tissues during endurance training.
A comprehensive understanding of exercise therefore requires investigating the organism as an integrated system rather than focusing exclusively on skeletal muscle.
Exercise, Metabolic Resilience, and Chronic Disease
The concept of physiological resilience refers to the capacity of an organism to respond to challenges, maintain essential functions, and recover appropriately.
Physical training can improve several capacities relevant to resilience.
Greater aerobic fitness can reduce the relative physiological cost of everyday activities.
Increased muscular strength can improve independence and task performance.
Improved metabolic regulation can support management of conditions such as type 2 diabetes.
However, resilience is multidimensional.
No exercise program can eliminate all disease risks.
Similarly, high athletic performance does not guarantee optimal health in every domain.
The objective is to strengthen clinically meaningful capacities while recognizing individual limitations.
How This Research Informs Move Well
Our Move Well philosophy recognizes skeletal muscle as both a mechanical and biologically active tissue.
We therefore evaluate movement and physical fitness not only as performance characteristics but as components of broader health.
Programs may incorporate resistance training, aerobic conditioning, mobility work, and task-specific exercise according to clinical needs.
We also recognize that rehabilitation and exercise prescription should be adapted for individuals with chronic medical conditions.
However, we do not assume that measuring experimental exerkines is necessary to deliver effective care.
The most reliable indicators of program success remain meaningful changes in function, symptoms, exercise capacity, and relevant medical outcomes.
Molecular research helps explain why movement matters.
Clinical assessment helps determine what a particular individual needs.
Conclusion: The Body Communicates Through Movement
Skeletal muscle is more than a system of levers that moves bones.
It is an active participant in whole-body physiology.
When muscles contract, they initiate cellular responses and contribute to the release of signaling molecules capable of influencing other tissues.
These processes may participate in metabolic regulation, immune function, neurological health, and adaptation.
However, the science of exerkines is still developing.
Identifying a molecule released during exercise does not automatically establish its clinical significance.
And replicating one molecular signal does not reproduce the full biological effects of physical activity.
The most important lesson is that exercise works through a network of interacting processes.
Movement communicates with the body, and repeated movement can help the body become more capable of meeting future demands.
This is why exercise deserves a central place in preventive healthcare, rehabilitation, and long-term wellness.
Research References
Chow LS, Gerszten RE, Taylor JM, et al. Exerkines in health, resilience and disease. Nature Reviews Endocrinology. 2022;18:273–289. https://doi.org/10.1038/s41574-022-00641-2
Walzik D, Wences Chirino TY, Zimmer P, Joisten N. Molecular insights of exercise therapy in disease prevention and treatment. Signal Transduction and Targeted Therapy. 2024;9:138. https://doi.org/10.1038/s41392-024-01841-0
Pedersen BK. Physical activity and muscle–brain crosstalk. Nature Reviews Endocrinology. 2019;15:383–392. https://doi.org/10.1038/s41574-019-0174-x
Fiuza-Luces C, Valenzuela PL, Gálvez BG, et al. The effect of physical exercise on anticancer immunity. Nature Reviews Immunology. 2024;24:282–293. https://doi.org/10.1038/s41577-023-00943-0
MoTrPAC Study Group. Temporal dynamics of the multi-omic response to endurance exercise training. Nature. 2024;629:174–183. https://doi.org/10.1038/s41586-023-06877-w
Courneya KS, Vardy JL, O'Callaghan CJ, et al. Structured exercise after adjuvant chemotherapy for colon cancer. New England Journal of Medicine. 2025;393:13–25. https://doi.org/10.1056/NEJMoa2502760