Tryptophan-Kynurenine Metabolites in Exercise and Mental Health

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-1 alpha 1, 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 stress-induced 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.