Anna Bergquist

Introduction: Mental illness accounts for around 32.4% of the total number of years lived with a disability worldwide, with depression and anxiety disorders being the first and sixth leading causes of disability respectively.¹ The NIH states that 7.1% of U.S. adults experienced major depressive disorder and 2.7% of U.S. adults experienced generalized anxiety disorder in the past year.^2,3 Physical activity can help diminish the debilitating effects of many mental health disorders.⁴ Physical activity promotes the metabolism of kynurenine in skeletal muscle and the upregulation of β-catenin in the hippocampus to promote anxiolytic and antidepressive effects in the brain. Methods: To analyze the effects of β-catenin, rat pups were split into five groups: a control group, exercise group, maternal separation group, maternal separation and exercise group, and maternal separation and selective serotonin reuptake inhibitor fluoxetine-treated group.⁵ Maternal separation induced anxiety in rat pups.⁵ The rat pups in the exercise groups were scheduled to run on a treadmill for 30 minutes once a day for 10 days, starting on postnatal day 21.⁵ Expression of serotonin, a neurotransmitter, and tryptophan hydroxylase, a rate-limiting enzyme in the serotonin synthesis, in the dorsal raphe were analyzed through immunohistochemistry and western blot.⁵ To analyze kynurenine metabolism in skeletal muscle, participants completed a supervised 12-week progressive exercise program.⁶ Each week, participants performed two resistance training sessions and one high-intensity interval training session.⁶ Muscle biopsy was obtained and RNA isolation, reverse transcription, and quantitative PCR was performed to analyze levels of kynurenine aminotransferases, enzymes that promote kynurenine breakdown.⁶ Plasma kynurenine was analyzed with ELISA.⁶ Results: Separation was found to suppress phosphorylation of glycogen synthase kinase 3 beta (GSK3β) and increase phosphorylation of β-catenin in the hippocampus, leading to symptoms of anxiety and depression.⁵ Treadmill exercise enhanced GSK3β phosphorylation and suppressed β-catenin phosphorylation in the hippocampus.⁵ Upregulation of β-catenin caused increased transcription in the nucleus of neural tissue, reducing inflammation and promoting synthesis of essential neurotransmitters such as serotonin.⁵ Exercise upregulates the PGC-1α1-PPARa/d pathway, increasing skeletal muscle expression of kynurenine aminotransferases, and thus enhancing the conversion of kynurenine into kynurenic acid.⁶ Kynurenic acid cannot cross the blood-brain barrier and therefore cannot induce depression-like symptoms in the central nervous system.⁶ Conclusion: Exercise enhances the effects of β-catenin in the hippocampus and promotes the breakdown of kynurenine in skeletal muscle. β-catenin increases the expression of myelin-based protein and other factors that promote neurogenesis to diminish depressive and anxious symptoms.⁷ Exercise has been found to increase transcriptional factors that break down kynurenine and therefore prevent it from causing depression and anxiety.

1. Kandola A, Ashdown-Franks G, Stubbs B, Osborn DPJ, Hayes JF. The association between cardiorespiratory fitness and the incidence of common mental health disorders: A systematic review and meta-analysis. J Affect Disord. 2019;257:748-757. doi:10.1016/j.jad.2019.07.088
2. NIMH: National Insitute of Mental Health. Major depression. https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Published February 2019. Accessed March 3, 2021.
3. NIMH: National Institute of Mental Health. Generalized Anxiety Disorder. National Institute of Mental Health. https://www.nimh.nih.gov/health/statistics/generalized-anxiety-disorder.shtml. Published November 2017. Accessed March 3, 2021.
4. Hu S, Tucker L, Wu C, Yang L. Beneficial Effects of Exercise on Depression and Anxiety During the Covid-19 Pandemic: A Narrative Review. Front Psychiatry. 2020;11:587557. Published 2020 Nov 4. doi:10.3389/fpsyt.2020.587557. November 2017. Accessed March 3, 2021.
5. Wang LR, Kim SH, Baek SS. Effects of treadmill exercise on the anxiety-like behavior through modulation of GSK3β/β-catenin signaling in the maternal separation rat pup. J Exerc Rehabil. 2019;15(2):206-212. Published 2019 Apr 26. doi:10.12965/jer.1938094.047
6. Allison DJ, Nederveen JP, Snijders T, et al. Exercise training impacts skeletal muscle gene expression related to the kynurenine pathway. Am J Physiol Cell Physiol. 2019;316(3):C444-C448. doi:10.1152/ajpcell.00448.2018
7. Cheng J, Shen W, Jin L, et al. Treadmill exercise promotes neurogenesis and myelin repair via upregulating Wnt/β‑catenin signaling pathways in the juvenile brain following focal cerebral ischemia/reperfusion. Int J Mol Med. 2020;45(5):1447-1463. doi:10.3892/ijmm.2020.4515