A study recently published in Cell has made a molecular link between exercise and resistance to depression (Cell 159, 33–45, 2014).
It is known that exercise induces expression of the transcriptional coactivator PGC-1a in muscle. Aguedlo et al. showed that mice in which PGC-1α is overexpressed in muscle (mck-PGC1-α1) are resilient to developing depression-like behavior induced by chronic mild stress (CMS) and associated changes in neuroinflammation and synaptic proteins. Depression has been linked to the conversion of tryptophan to kynurenine. Mck-PGC1-α1 mice had increased expression of KAT enzymes, which convert kynurenine to kynurenic acid. These mice also had lower levels of kynurenine in response to CMS, suggesting that increased kynurenine metabolism mediates resilience in these animals. Furthermore, kynurenine administration in wild-type mice induced depression-like behavior. Mice lacking PGC1-α1 in muscle also had increased depression-like behavior and circulating kynurenine levels, even in the absence of CMS. The authors also showed in cell culture experiments that the stress-induced transcriptional activators PPAR-α and PPAR-δ are binding partners of PGC1-α.
Endurance training in mice increased expression of PGC-1a and KAT enzymes in muscle, and increased plasma kynurenic acid levels. Furthermore, a 3-week training program in humans increased muscle expression of KAT enzymes, PPAR-α and PPAR-δ. This suggests exercise-induced changes in kynurenine metabolism could also occur in humans, and so may explain the beneficial effects of exercise in depressed patients.
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Stower, H. Linking exercise and depression. Nat Med 20, 1241 (2014). https://doi.org/10.1038/nm.3753