Tryptophan-Kynurenine Metabolites in Exercise and Mental Health

Abstract

In our efforts to identify molecular mediators of the benefits of exercise to human health, we have uncovered a biochemical pathway in skeletal muscle that positively impacts mental health. This mechanism is activated by endurance training and controlled by the transcriptional coactivator PGC-1α1, which induces transcription of several kynurenine aminotransferase (KAT) genes in muscle. KAT enzymes catabolize the neuroinflammatory tryptophan metabolite kynurenine, which can accumulate in the brain and lead to alterations associated with stressinduced depression (among other psychiatric diseases). Here, we discuss our findings in the context of what is known about the kynurenine pathway of tryptophan degradation and how its many metabolites can directly affect the brain. These findings provide a mechanism for how physical exercise can improve mental health and offers potential therapeutic targets for future antidepressant medications.

Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

“…Besides, the gut IDO-AhR signaling axis is critical in immunomodulation and immunotolerance that may be a critical target in reducing the burden of chronic inflammation [ 92 ]. Gut bacteria sequester Trp and produce indole related compounds that are also AhR agonists [ 295 ]. Drug development strategies to sequester excess peripheral kynurenine by gut microbiota could interrupt the flux of KP precursors towards the brain.…”

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

“…Increased muscle use of branched-chain amino acids (BCAAs) favors the passing of Trp through the blood-brain barrier (277). In addition, endurance exercise increases concentrations of circulating free fatty acids, which displaces Trp from albumin, thus increasing free Trp concentrations (278). Additionally, physical activity increases the expression of kynurenine aminotransferases, which enhance the conversion of Kyn into KYNA (unable to cross the bloodbrain barrier), thus protecting the brain from stress-induced changes (279).…”

The Influence of Exercise Intensity on Tryptophan Metabolites in Thoroughbred Horses

“…Additionally, the reported increased activity of KAT in exercised muscles results in Kyn transformation to the anti-depressant kynurenic acid and prevents the accumulation of Kyn in peripheral tissues. Thus, Kyn penetration into the brain is inhibited, preventing subsequent depression-inducing consequences [ 7 ]. On the other hand, an increase in XA and NAm levels reported in the present study might have neuroprotective and anti-depressive effects.…”

“…Both mentioned Trp catabolism pathways are modulated by physical activity [ 6 , 7 ]. In athletic horses, significant increases in plasma Trp, 5-HT, Kyn, Kyna and XA in response to different types of exercise were reported [ 8 , 9 , 10 , 11 , 12 ].…”