Introduction: The Hidden Language of Exercise

We have all heard that exercise is good for us. It helps us stay fit, boosts our mood, and keeps our hearts healthy. 

But have you ever wondered how these benefits actually occur at the cellular level? 

Enter exerkines, the fascinating molecules that act as messengers between physical activity and physiological transformation.

In this blog article, we will dive into the emerging science of exerkines and explore how these tiny molecules are changing our understanding of exercise’s impact on health. 

Whether you are a fitness enthusiast or someone who is just curious about how your body works, get ready to discover the  ways your workout routine is secretly talking to your cells.

The Discovery of Exerkines

The concept of exerkines is relatively new in scientific research. Scientists have long known that exercise has wide-ranging benefits, but the exact mechanisms were not always clear. The discovery of exerkines has helped fill in many of these gaps in our understanding.

Researchers began to notice that when people exercised, there were changes in their blood composition that could not be explained by traditional exercise physiology. This led to the identification of various molecules that seemed to appear or increase during physical activity. As studies progressed, it became clear that these molecules were playing a crucial role in how exercise benefits our health.

What Are Exerkines?

Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. 

Exerkines are defined as signalling molecules released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). 

Essentially, exerkines serves as the body’s way of communicating the benefits of exercise to different systems, translating physical activity into systemic health improvements.

Exerkines have potential roles for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. 

Types of Exerkines and Their Functions

There are many different types of exerkines, each with its own specific functions. Biochemically, exerkines can be hormones, metabolites, peptides, proteins, lipids, and nucleic acids.

Some of the most well-studied exerkines include:

• Myokines: These are proteins produced and released by muscle cells during contraction. Examples include interleukin-6 (IL-6) and irisin.
• Adipokines: These are produced by fat tissue and can be influenced by exercise. Adiponectin is an example of an adipokine that increases with exercise.
• Hepatokines: These are produced by the liver in response to exercise. Fibroblast growth factor 21 (FGF21) is a hepatokine that plays a role in metabolism.

Each of these exerkines has specific effects on different parts of the body. For example, some might influence fat burning, while others could affect brain function or bone health.

How Exerkines Work: The Body’s Exercise Communication Network

The Exercise-Induced Signalling Cascade

Exercise is more than just burning calories.

When you start exercising, your body goes through a series of changes. Your heart rate increases, you breathe faster, and your muscles start working harder. But at a molecular level, something even more interesting is happening – your muscles are starting to produce exerkines.

Key Exerkines and Their Functions

When you exercise, your body releases a host of beneficial molecules known as exerkines. These signalling compounds play a crucial role in maintaining overall health by regulating metabolism, reducing inflammation, supporting brain function, and more. 

Here is an overview of some key exerkines and their functions:

IL-6 (Interleukin-6)

What it does: IL-6 was one of the first myokines discovered. It is a multifunctional molecule that acts as an anti-inflammatory during exercise, helps mobilise energy, and plays a key role in metabolic regulation.

How it works: IL-6 is released in response to stress, injuries, or infections. It supports the immune system by stimulating inflammation when needed and aiding tissue repair.

Irisin

What it does: Released during muscle contraction, irisin promotes the transformation of white fat (which stores energy) into brown fat (which burns energy). It also improves glucose metabolism and reduces inflammation.

Why it matters: Irisin is linked to better blood sugar control and fat burning, making it a key player in metabolic health.

Brain-Derived Neurotrophic Factor (BDNF)

What it does: Exercise increases levels of BDNF, a molecule that supports brain health by encouraging the growth of new neurons and protecting existing ones.

Why it matters: Higher BDNF levels are associated with improved cognitive function, better mental health, and resistance to oxidative damage.

Fibroblast Growth Factor 21 (FGF21)

What it does: This exerkine regulates energy balance, improves cholesterol and lipid profiles, and has anti-inflammatory effects.

When it is released: FGF21 levels rise after moderate-intensity exercise, supporting metabolic health and energy regulation.

Apelin

What it does: Apelin helps regulate metabolism and cardiovascular function. It improves glucose homeostasis and adapts skeletal muscle to exercise.

Why it is important: Its release during exercise enhances the body’s ability to process sugar and adapt to physical activity.

Adiponectin

What it does: Secreted by fat cells, this exerkine improves insulin sensitivity and has anti-inflammatory effects.

Key benefit: Adiponectin plays a critical role in preventing metabolic disorders like diabetes.

Myostatin (MSTN)

What it does: Myostatin limits muscle growth, but its levels drop during exercise, enabling muscle building and repair.

Why it matters: Suppressing myostatin through exercise supports muscle growth and reduces inflammation.

Lactate

What it does: Commonly associated with muscle fatigue, lactate is also a signalling molecule. It can cross the blood-brain barrier, where it promotes brain plasticity and supports the release of BDNF.

Surprising benefit: Lactate plays a vital role in brain health and adaptation to exercise.

Secreted Protein Acidic and Rich in Cysteine ( SPARC)

What it does: SPARC encourages the “browning” of white fat, making it more metabolically active. It also reduces inflammation.

Why it is useful: It enhances lipid metabolism, which supports weight management and overall health.

MicroRNAs (miRNAs)

What they do: These tiny molecules regulate gene expression, helping the body adapt to exercise.

Emerging role: Research suggests miRNAs influence everything from inflammation to muscle repair.

Endocannabinoids

These natural chemicals create the “runner’s high” and help reduce anxiety and pain.

Together, these exerkines and molecules highlight why exercise is so beneficial for both the body and mind. Regular activity triggers a cascade of responses that improve physical and mental health, offering long-term protection against chronic diseases.

Exerkines and Their Role in Metabolic Regulation and Inflammation

Exerkines, molecules released during and after exercise, play a vital role in regulating metabolism, reducing inflammation, and enhancing overall health. Here’s how these fascinating compounds influence the body:

• Glucose Uptake and Insulin Sensitivity

Exerkines such as IL-6, adiponectin, and irisin improve how muscles take up glucose and enhance insulin sensitivity.

Adiponectin, for example, activates AMPK (an enzyme crucial for energy balance) to promote glucose uptake and improve insulin response, helping prevent metabolic diseases like type 2 diabetes.

Exercise enhances pancreatic function, improving insulin secretion and sensitivity while supporting overall metabolic homeostasis.

• Fat Metabolism

Exerkines stimulate the breakdown of fat (lipolysis) and promote fatty acid oxidation, which generates energy and improves lipid profiles.

SPARC induces the “browning” of white adipose tissue, transforming it into metabolically active tissue that burns more energy, while IL-6 enhances fat breakdown.

• Mitochondrial Function

Exercise boosts mitochondrial biogenesis and function, increasing the efficiency of energy production in cells.

Apelin stimulates mitochondria formation through AMPK activation, ensuring better energy utilisation and endurance.

• Organ Cross-Talk

Exerkines act as messengers between organs, helping coordinate the body’s systemic responses to exercise.

Exerkines and Inflammation

• Anti-Inflammatory Effects

Regular exercise reduces chronic low-grade inflammation, and exerkines like IL-6 and irisin help shift the body into an anti-inflammatory state.

These molecules modulate immune cell activity and reduce the production of pro-inflammatory cytokines, protecting against inflammation-driven conditions like arthritis or cardiovascular diseases.

• Immune Modulation

Exercise influences immune cell behaviour, encouraging a shift towards an anti-inflammatory M2 macrophage phenotype.

This phenotypic change dampens overall inflammation and supports tissue repair.

• Cardiovascular Protection

Exerkines such as FGF-21 reduce inflammation in the cardiovascular system, protecting against atherosclerosis and other heart diseases.

These molecules improve lipid metabolism and help maintain vascular health.

Broader Benefits of Exerkines

• Neuroprotection and Brain Health

Many exerkines support brain health, promoting neuroprotection and cognitive function. For instance, lactate stimulates the release of BDNF, a molecule that encourages neuroplasticity and mental well-being.

• Tissue Repair and Regeneration

Exerkines promote recovery by stimulating cell repair and regeneration, enhancing the body’s ability to heal after exercise.

• Therapeutic Potential

Exerkines are emerging as potential targets for pharmaceuticals that mimic the benefits of exercise. They offer hope for treating conditions like metabolic syndrome, neurodegenerative diseases, and inflammation-related disorders.

Why Exerkines Matter?

Exerkines represent a critical link between physical activity and improved health. By regulating metabolism, reducing inflammation, and protecting vital organs, they highlight the profound benefits of regular exercise for the body and mind. These molecules also offer exciting possibilities for future therapies aimed at mimicking the positive effects of exercise, bringing hope to individuals unable to engage in regular physical activity.

Optimising Your Exercise for Exerkine Production

Types of Exercise and Exerkine Release

Different types of exercise can stimulate the production of different exerkines. While all forms of exercise are beneficial, some may be particularly effective for certain health goals:

• Aerobic Exercise: Activities like running, cycling, or swimming are great for producing a wide range of exerkines, particularly those associated with cardiovascular health and metabolism. Aerobic exercise may lead to greater increases in certain myokines such as irisin and FGF21, while anaerobic exercise stimulates the production of lactate and myokines such as IL-7 and IL-8.
• Anaerobic exercise stimulates the production of lactate and myokines such as IL-7 and IL-8.
• Resistance Training: Weightlifting and bodyweight exercises can stimulate the production of exerkines associated with muscle growth and bone health.
• High-Intensity Interval Training (HIIT): This type of exercise, which involves short bursts of intense activity followed by periods of rest, has been shown to be particularly effective at stimulating the release of certain exerkines like IL-6 and irisin. 
• Moderate-intensity training is an effective exercise for increasing apelin levels.

Duration and Intensity: Finding the Sweet Spot

The amount and intensity of exercise needed to optimise exerkine production can vary. Some studies suggest that:

• Moderate-intensity exercise for at least 30 minutes can significantly increase exerkine levels.
• High-intensity exercise, even for shorter durations, can lead to substantial exerkine release.
• Regular, consistent exercise is key to maintaining the benefits of exerkines over time.

It is important to note that more is not always better. Overtraining can actually lead to negative effects, so it’s crucial to find a balance that works for your body.

Time of Day/Circadian Clocks: Tissue sensitivity and response to exercise vary according to time of day and the alignment of circadian clocks, but the optimal exercise time to elicit a desired metabolic outcome is not fully defined.

Individual Variability: There is considerable interindividual variation in exerkine secretion in response to exercise. “Non-responders” to exercise suggest complex underlying cellular mechanisms, and further studies are necessary to understand this.

Timing Matters

The release of exerkines follows specific patterns:

• Some are released during exercise
• Others peak immediately after exercise
• Still others show elevated levels for hours or even days afterwards.
• This is why consistent, regular exercise is more beneficial than occasional intense workouts – it helps maintain optimal levels of these beneficial molecules.

Exerkines and Male Infertility

• Improved Sperm Quality: Studies suggest that physical activity positively impacts sperm quality. Paternal preconceptional physical activity can induce changes in sperm miRNAs and DNA methylation.
• Moderate and regular exercise can be beneficial in male fertility by modulating anti-inflammatory and antioxidative mechanisms.
• Reduced Inflammation: Exercise can reduce inflammatory markers in semen, improving sperm DNA integrity.
• Oxytocin: High-intensity interval exercise can increase plasma oxytocin levels, which may also play a role in male fertility.
• Interestingly, repeated high-intensity interval exercise (HIIE) was found to increase plasma oxytocin (OT) levels in healthy men.

Brain Health and Cognitive Function

Perhaps one of the most exciting areas of exerkine research is their impact on brain health. Studies have shown that certain exerkines can:

• Promote the growth of new brain cells
• Improve memory and learning
• Potentially protect against neurodegenerative diseases

BDNF increases in response to exercise and has been linked to improved cognitive function and a reduced risk of conditions like Alzheimer’s disease.

Bone Health

Exerkines also play a crucial role in maintaining strong bones and muscles. They can:

• Stimulate bone formation
• Enhance muscle growth and repair
• Improve muscle strength and endurance

For example, the myokine osteocrin has been found to promote bone growth, potentially helping to prevent conditions like osteoporosis.

Exerkines and Disease Prevention

Cancer Prevention and Treatment

Emerging research suggests that exerkines may play a role in both preventing and treating cancer. Some studies have found that exerkines can:

• Inhibit the growth of cancer cells
• Enhance the effectiveness of cancer treatments
• Reduce inflammation associated with cancer

While more research is needed, these findings open up exciting possibilities for using exercise as part of cancer prevention and treatment strategies.

Diabetes Management

Exerkines have shown promising effects in managing diabetes. They can:

• Improve insulin sensitivity
• Help regulate blood sugar levels
• Reduce inflammation associated with diabetes

For example, the exerkine IL-6, when released during exercise, has been found to increase glucose uptake and fat oxidation, potentially helping to manage blood sugar levels in people with diabetes.

Aging and Longevity

As we age, our bodies produce fewer beneficial exerkines. However, regular exercise can help maintain exerkine production, potentially slowing down some aspects of aging. Exerkines have been linked to:

• Improved cellular health
• Better DNA repair
• Enhanced mitochondrial function

These effects could contribute to healthier aging and potentially even increased longevity.

The Future of Exerkine Research

While these applications are still in the early stages of research, they hold promise for revolutionising how we approach health and disease prevention.

Several challenges need to be addressed:

• Complexity: The interaction between exerkines and their target tissues is highly complex, making it difficult to pinpoint specific mechanisms.
• Individual Variability: Factors such as age, genetics, and fitness level influence exerkine production, complicating their application in personalised medicine.
• Delivery Methods: Developing effective ways to administer exerkine-based therapies remains a significant hurdle.

Potential Therapeutic Applications

• Exercise-Mimicking Pharmaceuticals: Exerkines may offer targets for developing pharmaceuticals that mimic the benefits of exercise.
• Personalised Exercise Prescriptions: Understanding the kinetics and dynamics of exerkine release will help to develop personalised exercise prescriptions.
• Blood Biomarker Profiling: Blood biomarker profiling during exercise, combined with information from wearable sensors, will allow for real-time monitoring of metabolic and inflammatory responses. The combination of wearable devices and multi-omics microsampling during physical exercise will facilitate the dynamic profiling of sports-related health status.
• Therapeutic Interventions: Exerkines have therapeutic potential for conditions such as metabolic disorders, cardiovascular diseases, and neurological disorders (e.g., Alzheimer’s), through their effects on inflammation, neuroprotection, and metabolism.
• Microbiome: The role of the gut microbiome in mediating exercise-induced adaptations is another avenue for research. Microbiome transplants from trained donors can improve skeletal muscle disuse atrophy.
  

Despite these challenges, ongoing research holds promise for uncovering more about these powerful molecules.

Conclusion: The Power of Movement

As research continues, we can expect to gain a clearer understanding of how to best harness the power of exerkines for health.

The emerging science of exerkines provides a fascinating glimpse into the intricate ways our bodies respond to exercise. These molecular messengers help explain why physical activity has such wide-ranging benefits, from improving heart health to boosting brain function and potentially even fighting cancer.

While there is still much to learn about exerkines, one thing is clear regular exercise is one of the most powerful tools we have for promoting health and preventing disease. By understanding how exercise communicates with our bodies at a molecular level, we can better appreciate the true value of staying active.

So the next time you lace up your running shoes or hit the gym, remember that you are not just burning calories or building muscle. You are activating a complex network of molecular messengers that are working to improve your health in countless ways. It is a powerful reminder that every step, every lift, and every stretch is an investment in your long-term health and well-being.

As research in this field continues to evolve, we can look forward to even more insights into how to optimise our exercise routines for maximum health benefits. In the meantime, keep moving – your body, down to its very cells, will thank you for it.

References

Zhou N, Gong L, Zhang E, Wang X. 2024. Exploring exercise-driven exerkines: unraveling the regulation of metabolism and inflammation. PeerJ 12:e17267 DOI 10.7717/peerj.17267

Watkins, B.A.; Smith, B.J.; Volpe, S.L.; Shen, C.-L. Exerkines, Nutrition, and Systemic Metabolism. Nutrients 2024,16,410. https:// doi.org/10.3390/nu16030410

Novelli, G.; Calcaterra, G.; Casciani, F.; Pecorelli, S.; Mehta, J.L. ‘Exerkines’: A Comprehensive Term for the Factors Produced in Response to Exercise. Biomedicines 2024, 12, 1975. https://doi.org/10.3390/ biomedicines12091975

This article is not intended to replace professional medical advice. If you have specific health concerns or conditions, consult with a healthcare professional for personalised guidance.

Disclaimer: The information provided in this article is for educational purposes only and should not be considered as medical advice. Always consult with a healthcare professional before making any changes to your diet or lifestyle.