In 2000, scientists first discovered that muscle contractions release exercise-associated signaling molecules. Since then, many other such molecules have risen to the forefront of research. Exerkines, defined as signaling molecules released in response to acute/chronic exercise, exert their effects through endocrine and various other pathways. In this article, we will explore the intricacies of signaling molecules, focusing on exerkines and the benefits they may confer on health and age-related disease.
Understanding the Release of Exerkines
Regular exercise and physical activity are common lifestyle factors that can confer positive effects on human health. Physical activity reduces disease burden, protects against the onset of certain pathologies, and improves disease course. Unlike drug-related therapies, exercise effects do not limit themselves to a specific target organ; instead, they act on multiple biological systems simultaneously. Despite the substantial health benefits of physical training, the precise molecular signaling processes that lead to structural and functional adaptation remain largely ill-defined, working on levels unseen by the human eye.
Scientists have only recently identified several bioactive molecules released during moderate to intense physical exercise. These molecules, collectively referred to as “exerkines”, are released from various tissues in response to muscular contraction and play a crucial role in mediating the beneficial effects of exercise on the body.
Major discoveries involving exerkines focus on their diverse functions and health implications, particularly in metabolic regulation, neuroprotection, and muscle adaptation. These molecules, which include peptides, nucleic acids, lipids, and microRNAs, among others, act through various bodily pathways to exert their effects on various organs and tissues.
Similarly, exerkines may play a role in improving cardiovascular health. As such, scientists have begun exploring the use of exerkines to treat cardiovascular disease, type 2 diabetes, and obesity, and possibly to support healthy aging.
Tapping Into Exerkines’ Therapeutic Benefits on the Skeletal System
The integration of exercise-induced exerkines into therapeutic strategies represents a promising approach to mitigating a variety of age-related pathologies at the molecular level. As scientists gain a deeper comprehension of such mechanisms, it may pave the way for personalized interventions that could perhaps leverage/manipulate physical exercise in an effortto enhance/ improve one’s quality of life.
Personal trainers often witness the unfortunate situation of sarcopenia in their older adult clients, characterized by the progressive and generalized loss of skeletal muscle mass and strength. Exercise has proven itself many times over as an effective intervention for sarcopenia. In particular, the release of exerkines during physical activity confers beneficial effects on the body; these benefits have sparked interest in whether exerkines in particular may offer a novel therapeutic strategy for understanding the manners in which exercise enhances skeletal muscle mass/function.
Exerkines exert protective effects on aging skeletal muscle primarily through the combined effect of the following mechanisms:
- Mediating energy diversion to skeletal muscle, ensuring the delivery of a sufficient energy supply
- Enhancing the activity of skeletal muscle satellite cells to promote muscle repair and regeneration
- Upregulating the expression of genes associated with muscle regeneration while simultaneously inhibiting the expression of those genes responsible for the atrophy of skeletal muscle
- Improving the function of the neuromuscular junction to improve neural control of skeletal muscle
Enhancing and Regulating Metabolic Wellness
Exerkines can also affect the metabolic system, regulating metabolic homeostasis by increasing glucose uptake and improving fat synthesis. In a related area of interest, exerkines also exert anti-inflammatory effects, positively influencing chronic inflammation-related diseases such as type 2 diabetes and atherosclerosis. For these reasons, much of the scientific literature on this topic now focuses on the prospective contribution of exerkines in regulating metabolism, augmenting anti-inflammatory effects, and providing additional exercise-related benefits. As with the aforementioned skeletal enhancement, researchers also predict that future applications might include using exerkines as a potential biomarker or therapeutic target to benefit patients with chronic metabolic/inflammatory-related diseases.
Different Modes of Exercise Elicit Different Exerkine Secretions
Because different bodily tissues—skeletal muscle, liver, and fat—secrete distinct exerkines, a multifaceted approach to movement can maximize their systemic benefits. Exerkines are secreted in response to acute exercise exposure — usually a single aerobic or resistance exercise episode — as well as chronic, multi-day exercise routines. Chronic exercise also elicits exerkine production during the post-exercise recovery/rest period. Exerkine responses seem influenced by exercise type, duration, underlying fitness level, and fed-fasting timing following exercise.
Typically, acute exercise aligns with exerkine-produced responses focused on metabolic homeostasis, anti-inflammatory mediators, and shifts in fuel use from carbohydrates to fat. In contrast, chronic exercise fosters exerkine-produced responses focused on long-term metabolic adaptations and decreased inflammation. When investigating chronic exercise exposure, scientists acknowledge the need to control many variables, such as recent dietary composition, fitness level, fed-fasting status, circadian timing, and training modality. Future use of exercise/exerkine release as therapeutic options will have to take all of these variables into account before validating prescriptions for such.
Designing Workouts to Take Advantage of Specific Exerkine Release
While much of the biochemistry associated with an average client’s workout largely belongs to the realm of the scientific community, personal trainers can attempt to adapt sessions to accommodate a client’s potential health needs. Below we outline a few suggestions:
High-Intensity Interval Training (HIIT)
This type of workout involves vigorous, short bursts of activity that trigger a massive, rapid release of exerkines due to intense metabolic stress, typically interleukin-6 (IL-6) and lactate. When released by muscle contractions, IL-6 acts as a powerful anti-inflammatory driver, improving insulin sensitivity while encouraging the body to burn fat tissue. Lactate acts as both an energy substrate and a signaling molecule that can cross the blood-brain barrier.
Clients can engage in 20 to 30 minutes of exercise, alternating between 30–60 seconds of maximum effort (sprinting, cycling, or aggressive rowing) and periods of active recovery.
Progressive Resistance Training
Heavy resistance training creates mechanical tension that forces skeletal muscles to release abundant muscle-specific exerkines known as myokines. An intense strength training session releases FGF-21 (fibroblast growth factor 21) and IL-15. FGF-21 regulates both fat and glucose metabolism, while Interleukin-15 supports mitochondrial health and tissue “youthfulness”, including taut skin and firm muscles.
Personal trainers can help clients encourage this process by focusing on large muscle groups 3 to 5 days a week using free weights, machines, or resistance bands. Strive for intensities somewhere between 70% and 90% of the client’s one-rep max (1RM), as this range seems best at optimizing post-exercise exerkine spikes.
Sustained Aerobic Exercise (Endurance)
Longer, steady-state cardiovascular exercise triggers the expression of transcription factors required for cellular restructuring and long-term metabolic health. Sustained exercise activates a substance called PGC-1 alpha, which forces the production and subsequent cleavage of a specific protein that releases irisin. Irisin plays a vital role in turning white adipose tissue into the more favorable calorie-burning brown fat. Irisin also travels to the brain, where it triggers BDNF (brain-derived neurotrophic factor), a substance that supports better memory and overall cognitive health.
To ensure this process works effectively, trainers can encourage clients to get 150 minutes a week of moderate-intensity activity, such as brisk walking, cycling, or swimming.
Exerkines May Counteract Senescent Cognitive Decline
As the human body ages, the adult brain changes at the molecular, functional, and cellular levels. This, in turn, often leads to regenerative decline, cognitive impairment, and a predilection for dementia-related conditions like Alzheimer’s disease.
We know that exercise helps alleviate age-related cognitive impairment, but the underlying mechanisms remain poorly understood. To clarify this, one study placed 6-month-old mice on running wheels and found that muscle-derived exerkines positively correlated with biological pathway scores linked to improved neurogenesis and cognition in the hippocampus. Additional studies have shown that platelet cells activate after periods of running, releasing factors like the chemokine platelet factor-4, which helps promote neurogenesis and cognitive rejuvenation.
Exerkines and the Gut Microbiome
So far, we have focused on the skeletal, metabolic, and cognitive aspects of the body and how exerkines can have beneficial effects. Not often considered in a discussion of exercise-related mediators, the liver actually serves as a source of many exercise-induced circulating proteins. These exerkines affect glucose and/or fat metabolism and can also alter the gut microbiome, regardless of one’s diet and body weight. The release of these exerkines depends on exercise intensity, modality, and duration. The mechanisms by which exerkines might alter the gut microbiome remain controversial, but some experts believe they alter the gene expression of several gut molecules to produce a more favorable anti-inflammatory profile, improve gut blood flow, or change bile acid excretion.
Contemporary research now recognizes exerkines as critical mediators of the exercise-related changes in health benefits, particularly in the role of inter-organ/systemic communication. Scientists have begun to investigate whether exerkines could someday serve as treatments for those individuals unable to exercise due to disability, frailty, and/or illness. The field remains wide open, requiring large-scale, structured studies to pursue exerkine-related answers that may predict exercise-produced outcomes, facilitate personalized exercise programs to improve health, ultimately reduce disease, and promote resilience across the lifespan. Overall, we understand that organs exhibit cross-talk in response to physical exertion. To demonstrate true efficacy in humans, research must continue to prove their validity.
References
michigantoday.umich.edu/2024/08/21/get-your-exerkines-before-its-too-late/
alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.083404
journals.physiology.org/doi/abs/10.1152/physiol.2026.41.S1.2323680
pmc.ncbi.nlm.nih.gov/articles/PMC10891799/
pmc.ncbi.nlm.nih.gov/articles/PMC11064867/
pmc.ncbi.nlm.nih.gov/articles/PMC11429193/
endocrinology.org/endocrinologist/144-summer-22/features/understanding-exerkines/
nature.com/articles/s41574-022-00641-2
frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1592491/full
sciencedirect.com/science/article/pii/S0531556525000130
pmc.ncbi.nlm.nih.gov/articles/PMC4269139/
