The Science of Running: Running and Depression

I'm starting my series on the Science of Running in scientific areas I'm more comfortable with. My research background is all Psychology and Neuroscience, so it seems pretty fitting. Now, mental health is a really difficult area. I am not in any way suggesting that a mental health disorder recovery is as easy as, 'just go a jog'. Mental health disorders are serious and debilitating and the research into them is totally fascinating. Today I'm just looking at just one research article connecting the two, and noting how it might actually work in plain English. I've deliberately chosen one that you won't see Runner's World commenting on, and that is hard to read for those not in science. I spotted it recently, and thought it was a really interesting approach. 

The paper I looked at was 'Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression' (2014) by Agudelo and colleagues. The lead researcher is Jorge L. Ruas who works at the Karolinska Institute in Sweden. See, that's a mouthful of a title. This is why no one apart from researchers, and their pals, ever read research articles. Ridiculous.

Okay so to clear up a few things in the title: the 'Kynurenine Metabolism' is a chemical pathway in the body, which can be activated by stress. It produces NAD+, an enzyme. This is manufactured from Tryptophan, an amino acid. NAD+ is involved the transfer of electrons from one molecule to another; the release of energy from nutrients; and as a novel neurotransmitter to communicate from nerves to effector cells in smooth muscle organs. Skeletal muscle-PGC-1α1 is a protein gene which mediates that pathway. Still with me?

In any human or mouse, exercise activates this Kynurenine Metabolism pathway, enhancing the conversion of Kynurenine to Kynurenic acid. Several of these Kynurenine outputs are associated with depression (higher levels of these = more likely to have depression). This mediation by exercise reduces Kynurenine plasma, and protects the brain from stress (as Kynurenine acid can't cross the blood brain barrier, but plasma could) and therefore has positive effects by reducing plasma-based brain change. So the importance is more acid, less other Kynurenine. PGC-1α1 also increases in skeletal muscle during exercise, so there is a dual effect of activation of the protein through exercise, and increase with muscle from consistent exercise.

So, more Kynurenine acid = better for your brain than Kynurenine plasma. 

To test this relationship, they then create mice that have more expression of the protein gene biologically. They find that these mice are resilient to stress-induced depression, as the gene induces Kynurenine Metabolism pathway expression - proof that the expression and creation of the acid has an effect on depression without the exercise. This is important because it proves causality in this pathway, not just correlation of the pathway activity and reduced depression chemicals. It also shows that PGC-1 α 1 controls plasma and the brain Kynurenine/Kynurenic acid balance. These mice are even resistant to straight injections of Kynurenine plasma

In layman's terms the muscles begin to act like the liver or kidneys and produce an enzyme, through this metabolic pathway, which clears out Kynurenine plasma linked to depression (by prioritizing the acid instead). There are a few caveats- this is tested in mouse stress induced depression (putting mice in a highly stressful environment and recording behavioural and stress hormone change). Whilst there are still parallels to human stress and depression (anxious environmental factors or high stress life events), there are some facets of clinical depression this does not mirror (day to day pervasive symptoms). Therefore take with consideration. However, stress is firmly linked to depression now, as inflammatory stress pathways modulate glutamate (a neurotransmitter) plasticity and transmission (both of which are very central to depression). The Kynurenine compounds mentioned also mediate glutamate and inflammatory circuits, probably in a negative way in the brain. So with more  Kynurenine acid compared to Kynurenine plasma, there is less effect on brain glutamate. 

Its fascinating how many things are going on inside us. We are a crazy mix of chemical relationships. On your next run, how about you have a think about your Kynurenine Metabolism?

If you are interested in running and mental health, check out this documentary footage of Simon Lamb bravely discussing his own issues with mental health and how running helped. He's amazing.


Have you ever been effected by issues of mental health in your running? No pressure to share obviously!

How was this to read, too techy? Too simplified?

Please note if anything in the above is incorrect, I'd love to hear about it, I'm keen to learn :-) Physiological Pharmacology, whilst connected, isn't my exact area. 


  1. Absolutely fascinating. My mum has suffered with bipolar all her life and has only now come out the other side, having been out of hospital for more than a year, the longest I can remember. Though this is through finally getting the cocktail of daily medsAbsolutely fascinating. My mum has suffered with bipolar all her life and has only now come out the other side, having been out of hospital for more than a year, the longest I can remember. Though this is through finally getting the cocktail of daily medsrather than exercise.

    1. So glad to hear your mum is recovering Tess. I think part of the difficulty of mental health is how incredibly varied treatment impacts can be on different people. Its great that your mum has found a set of interactive meds that are working well for her.

      I 100% don't think the conclusion of this paper is that exercise will cure all. I would say its conclusion is that for Kynurenine-mediated depression, this may help (part of the new theory set is that clients with the same mental health conditions/diagnoses, may actually have varying neural causes, particularly in Schizophrenia. This explains to some extent why different treatments work so differently on different people).

      Glad you found this interesting too :)