ENT.4 Physiological Effect of Exercise on Mental Health

It is well understood and known that there has been a significant global increase in mental health illnesses, specifically anxiety and depression, over the past few decades.[17] Many factors have been debated to explain this increase, from social media usage to technology in general or significant recent social and political pressures, such as the prevalence of negative news or the COVID-19 pandemic. One of these factors worth discussing is lifestyle and lifestyle change. In a 2020 study, it was found that only 24.2% of men and women met the federal recommended strength and aerobic fitness guidelines established in 2018.[4] This correlation may seem to be irrelevant; however, there does exist a significant relationship between mental and physical health. There are many key biological effects of physical exercise, both aerobic (cardiovascular) and strength training, that have been shown to have positive effects on mental health outcomes. Some of these direct biological effects of exercise,  discussed below, are the release of myokines from skeletal muscle and the effects of endorphins on the brain.

Myokines (BDNF, Irisin, IGF-1, IL-6, and CTSB)

Traditionally, myokines are a specific type of endocrine molecule, a subset of cytokines, or signaling molecules released by cells to other cells,  produced and released specifically by skeletal muscle, which have an effect on other organs and systems within the body.[14] These myokines are byproducts of muscular contraction and are therefore released in greater amounts during exercise, due to the increased load and force required. From a cellular standpoint, cytokines are released and absorbed as a means of communication, particularly within the immune and lymphatic system, but act as a form of communication within the body between organ systems. Understanding the relationship between myokines released during exercise helps us understand some of the extremely widespread benefits of exercise on nearly all of the organ systems in the human body, including the brain.

Some of the primary myokines that have effects on the brain and mental health include IL-6, CTSB, IGF-1, and Irisin. There are a few of these myokines that have a direct ability to cross the blood-brain barrier to have an effect on the brain, while some others have downstream effects on a common protein produced in the brain, BDNF. IL-6 is a myokine that has downstream effects on other proteins, causing an increase in the process of neurogenesis, the generation of new neurons, within the brain.[8] IL-6 does have the possibility to create an inflammatory response, possibly due to IL-6 trans signaling, a different pathway, due to its production as a cytokine instead of a myokine.[8] CTSB, released by skeletal muscle, has also been found to have associative effects on cognition, brain function, and the specific hippocampal function, which is the memory center of the brain.[5] CTSB also has an up-regulatory effect on BDNF production within the brain, bringing increases in positive effects on cognition through the increase in the effect of BDNF.[5] IGF-1 is an additional myokine that has both effects on increasing neurogenesis as well as downstream effects on the production of BDNF.[5] Irisin, released by skeletal muscle during exercise, is known to have effects on one of the BDNF signaling pathways within the brain as well.[11] Similar to CTSB and IGF-1, this causes a downstream effect leading to the upregulation of BDNF within the brain and subsequent effects.

BDNF is one of the leading and most influential proteins when it comes to neurogenesis within the brain and is therefore very important when it comes to discussing cognitive function and mental health. Low levels of BDNF have been associated with schizophrenia, major depressive disorder, general anxiety, parkinsons, multiple sclerosis, and Huntington's disease. [9,13,16,1] BDNF, however, has direct positive effects on the hypothalamus, hippocampus, and cortex of the brain, promoting functions such as learning, memory, and mood regulation.[3,1] As stated above, myokines such as CTSB, IGF-1, and Irisin activate signaling pathways leading to the increased production of BDNF within the brain and its associated downstream effects. It is clinically proven that there is an increase in production of BDNF within the brain as a result of exercise, therefore acting as a direct combatant to the mental health illnesses marked by low levels of BDNF, as well as producing numerous additional positive cognitive effects. BDNF’s effects on neurogenesis in the hippocampus, for example, directly lead to improvements in memory and the ability to learn.

Endorphin Release

Exercise released endorphin response is well established and often known by the common slang term exercise-induced euphoria.[6] Endorphins are chemical hormones produced by the body in response to a stressor and are associated with the brain's opioid receptors within its “reward” center.[6] The release of endorphins is associated with numerous psychological and physical responses, including changes in mood states, pain perception, and biological stress response.[6] Low levels of endorphins are shown to be associated with anxiety and dysregulation of endorphins that target opioid receptors, which may be associated with cases of depression.[12] One of the most prevalent ways to increase endorphin release within the brain is through exercise, specifically aerobic exercise, which can lead to a lasting effect of endorphin release, reducing stress.[7]

In addition to the direct effect of endorphin release on the reduction of sensations of stress and other mood regulation associated with anxiety and depression, there is a relationship between endorphin release and what is commonly referred to as the stress hormone. Cortisol levels have been shown to reduce proportionally with the introduction of endorphins within the body.[15] Endorphins seem to inhibit adrenocorticotropic hormone (ACTH), the direct signaling hormone produced in the pituitary gland that signals the adrenal gland to produce cortisol.[16] It is established in the literature that cortisol dysregulation is also directly associated with mood disorders, anxiety, and depression.[5] Therefore, through this pathway, exercise increases the release of endorphins within the body, inhibiting and regulating the production of cortisol and acting as a modulator to regulate the body's natural stress response.

Conclusion

In overview, there is a relationship between exercise and mental health that is worth exploring and worth acknowledging in a world where mental health illnesses are ever more prevalent. Exercise has a direct effect on cognitive function through a multifactorial approach, including but not limited to the release of myokines and endorphins. Low levels of BDNF are associated with mental health illnesses such as major depressive disorder and generalized anxiety.[9,13,16,1] Myokines such as CTSB, IGF-1, and Irisin have direct cognitive benefits as well as help to upregulate the production of BDNF, while IL-6, acting as a cytokine, has inflammatory effects.[8,10,11] Additionally, BDNF is directly stimulated by exercise and has effects on neurogenesis in the hypothalamus, hippocampus, and cortex, promoting functions such as learning, memory, and mood regulation.[3,1] Low levels and dysregulation of endorphins, as well as dysregulation of cortisol, are additionally associated with mood disorders, anxiety, and depression.[12,5] Yet, exercise is also shown to increase endorphin release, therefore reducing and regulating cortisol within the body, causing changes in mood states, pain perception, and biological stress response.[6,15] All of these biological and physiological effects of exercise go to further validate the fact that exercise has a direct positive effect on treating and combating mental illness through its diverse, multifaceted effects on the brain. This is facilitated by the exercise-stimulated release of both myokines and endorphins, which have direct effects on cognitive functions that combat those of common mental illnesses such as anxiety and depression within the brain. 

Exercise is vitally important to combating the increasing mental health crisis in the world today.

References

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[2] Cleveland Clinic. (2022, May 19). Endorphins: What They Are and How to Boost Them. Cleveland Clinic; Cleveland Clinic. https://my.clevelandclinic.org/health/body/23040-endorphins

[3] Correia, A. S., Cardoso, A., & Vale, N. (2023). BDNF Unveiled: Exploring Its Role in Major Depression Disorder Serotonergic Imbalance and Associated Stress Conditions. Pharmaceutics, 15(8), 2081. https://doi.org/10.3390/pharmaceutics15082081

[4] Elgaddal, N., Kramarow, E., & Reuben, C. (2022, August 29). Physical Activity Among Adults Aged 18 and Over: United States, 2020. Centers for Disease Control and Prevention. https://www.cdc.gov/nchs/products/databriefs/db443.htm

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[9] Lin, C.-C., & Huang, T.-L. (2020). Brain-derived neurotrophic factor and mental disorders. Biomedical Journal, 43(2), 134–142. https://doi.org/10.1016/j.bj.2020.01.001

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[11] Martinez Munoz, I. Y., Camarillo Romero, E. del S., & Garduno Garcia, J. de J. (2018). Irisin a Novel Metabolic Biomarker: Present Knowledge and Future Directions. International Journal of Endocrinology, 2018. https://doi.org/10.1155/2018/7816806

[12] Mental Health America. (2025, January 6). What are Endorphins? | Mental Health America. Mental Health America. https://mhanational.org/resources/what-are-endorphins/

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[15] Taylor, T., Dluhy, R. G., & Williams, G. H. (1983). Beta-endorphin suppresses adrenocorticotropin and cortisol levels in normal human subjects. The Journal of Clinical Endocrinology and Metabolism, 57(3), 592–596. https://doi.org/10.1210/jcem-57-3-592

[16] Wang, Y., Zhang, H., Li, Y., Wang, Z., Fan, Q., Yu, S., Lin, Z., & Xiao, Z. (2015). BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder. Journal of Affective Disorders, 186, 7–12. https://doi.org/10.1016/j.jad.2015.07.023

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