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Exercise is hard. It hurts. It makes you sweaty and requires you to stick to an exhausting routine in an already over-scheduled life. And, for years, psychiatrists have been telling their depressed patients to do a lot of it to help themselves feel better.
But, ironically, the very nature of the disease, including loss of motivation and an inability to stick to a routine, makes exercise as treatment seem impossible for many depression sufferers. Studies have shown that exercise reduces depressive symptoms, but scientists don’t know exactly why, which makes it hard to convince patients that the extra pain is actually worth it. Now, a new study has unearthed a clear mechanism that explains how exercise contributes to mental well-being under stress. Could it help doctors give patients a real reason to keep to their workout routines, or even lead to medications that never enter the delicate brain in the first place?
The new work, published in Cell, blossomed from ideas germinating in two labs at the Karolinska Institutet in Stockholm, Sweden: a neuroscience group led by Maria Lindskog and an exercise physiology lab led by Jorge Ruas. Both labs were very interested in understanding exercise’s role in reducing depression, but each approached it from different organs. So when Lindskog and Ruas met through a common friend, “We both realized that the combination of his mice and our models of depression would make a perfect match to answer these questions,” said Lindskog.
Ruas’ mice are so-called “marathon mice,” a transgenic variety overexpressing mck-PGC1alpha1. They have muscles that look as if they experienced an intense endurance exercise training program, but without ever having exercised. Their muscles have more blood vessels, the mice live longer, they are resistant to diabetes, and if you feed them a high-fat diet, they don’t become as fat as wild type (WT) mice. These transgenic mice have been used for years to study the effect of exercise on metabolic disease, obesity, and diabetes.
So, why not look at depression as well, especially as a way to isolate the role of muscle in reducing symptoms? The Lindskog lab had a strong working chronic mild stress (CMS) protocol, so the two teams merged and performed experiments together, investigating stress-induced depression on these transgenic mice. They exposed WT and transgenic mice to multiple unpredictable mild stressors such as loud sounds or strobe lights every day for 5 weeks, treatment that has been validated to produce symptoms of depression in mice, including increased immobility time in forced swim tests (a measure of despair) and decreased sucrose consumption (a measure of anhedonia, the inability to feel pleasure).
The team found that transgenic mice did not show symptoms of depression after experiencing this protocol, while WT mice did. Transgenic mice did still show decreases in body weight similar to WT mice.
To see whether there were differences in the brains of these mice, the researchers used Western blots to analyze brain synaptic proteins after the CMS protocol. WT mice showed less expression of proteins that mediate synaptic plasticity in the hippocampus, and glutamate receptor subunits were also altered after stress.
“I did get really surprised when we saw that none of the changes in synaptic proteins that we saw in WT happened in the PGC overexpression mice,” said Lindskog. Neurotrophic factors and structural synaptic genes shifted in WT mice after CMS as well, while remaining unchanged in transgenic mice.
“In all of these findings, we kept seeing the same thing: whatever happens to stressed WT mice never happens with muscle transgenics. So some mechanism was protecting the mice from being affected by the stress in terms of developing depression,” said Ruas.
In the Genes
To figure out the mechanism, the teams analyzed gene expression array data in mouse muscle with PGC1alpha1 overexpression, revealing a role for the protein in controlling the kynurenine pathway of tryptophan degradation. Converting tryptophan to kynurenine (KYN) is a key step in producing stress-induced depression. Using qRT-PCR to examine the expression levels of rate-limiting enzymes in the kynurenine pathway in skeletal muscle, they found high expression of kynurenine aminotransferase (KAT) in the transgenic mice, which CMS further increased.
KAT enzymes help convert KYN to kynurenic acid (KYNA). While KYN crosses the blood-brain barrier and is linked to stress-induced depression, KYNA cannot and is not. The researchers found high KYN levels in the plasma of WT mice exposed to CMS, but transgenic mice instead showed high plasma levels of KYNA. A metabolite of KYN was also found in high levels in the brains of stressed WT mice, but not transgenic mice. In addition, injecting KYN into WT mice led to depressive symptoms and the depressive pattern of gene expression, but not in transgenic mice.
“The trick is that kynurenine can cross from your blood to your brain and induce toxicity, depression. The acid form does not have this ability. So all of a sudden, you detoxify this burden to the brain by converting from one molecule to the other,” said Ruas.
To confirm their findings, the teams analyzed WT mice that had 8 weeks of free wheel running under their belt. This endurance training increased the KAT enzymes and plasma KYNA levels. Finally, the team exposed a group of human volunteers to a 3-week training program, testing their skeletal muscle before and after for KAT. The post-exercise humans also showed an increase in KAT.
“The big thing is to show that by changing something in the periphery of your body, in muscle, you can affect function in the brain. That was the big novelty of the paper,” said Ruas.
Exercise in a Pill
In Sweden, physicians prescribe exercise as a therapy. Ruas plans to follow some of these patients to verify the biochemical changes they found in the mice.
“On an average adult human being, muscle mass represents 35–40% of the whole body. So activating half of your body to detoxify a molecule like this, it will have an impact,” said Ruas. Endurance aerobic training, not just exercising, is the key. The researchers haven’t looked at resistance training, such as weight lifting, yet. And they want to see whether there’s any role in metabolism for KYNA.
Perhaps, someday, Ruas and Lindskog could even put exercise into a pill. “We can imagine a future class of antidepressants that could target your muscle instead of your brain and would help your body detoxify kynurenine and protect you from depression.” said Ruas.
Agudelo LZ, Femenía T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, Correia JC, Izadi M, Bhat M, Schuppe-Koistinen I, Pettersson AT, Ferreira DM, Krook A, Barres R, Zierath JR, Erhardt S, Lindskog M, Ruas JL. Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression. Cell. 2014 Sep 25;159(1):33-45.
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