Depression is a debilitating condition that affects millions of people worldwide. Physical exercise can improve symptoms in many people with depression, but the mechanisms by which it does so have not been characterized.

Physical endurance exercise induces PGC-1α1 in skeletal muscle, promoting mitochondrial biogenesis, fatty acid oxidation, angiogenesis and resistance to muscle atrophy. By studying young transgenic male mice overexpressing PGC-1α1 in skeletal muscle, researchers from Karolinska Institutet (Stockholm, Sweden) have now identified one way in which skeletal muscle PGC-1α1 induced by physical exercise protects against depression. Induction of PGC-1α1 increases the conversion of kynurenine into kynurenic acid, a metabolite that cannot cross the blood–brain barrier. Kynurenine in the brain is associated with inflammation, which is, in turn, correlated with depression. Reducing plasma kynurenine concentrations protects the brain from stress-induced changes associated with depression (Cell 159, 33–45; 2014).

Maria Lindskog and Jorge Ruas led the study, in which transgenic and control mice were exposed to chronic mild stress to induce depressive behavior. After 5 weeks, the control mice showed behavioral signs of anhedonia (less sucrose consumption) and despair (less locomotor activity during forced swim tests) and neurologic changes including decreased synaptic plasticity and imbalances in glutamate metabolism. The transgenic mice, however, showed no behavioral or neurological signs of depression. Exposure to chronic mild stress also increased plasma levels of kynurenine in control mice, but not in transgenic mice, which instead had higher plasma levels of kynurenic acid. Furthermore, administration of exogenous kynurenine resulted in increases in plasma levels of kynurenine and in altered behavior and gene expression in control mice but not in transgenic mice, which again had elevated levels of kynurenic acid instead. The scientists also evaluated behavior and gene expression in response to kynurenine administration in a separate group of transgenic mice lacking expression of PGC-1α1 in skeletal muscle. These mice showed signs of anhedonia under control conditions, which was worsened by kynurenine administration. Changes in gene expression and increases in plasma kynurenine levels greater than those observed in control mice in response to kynurenine administration were also noted in mice lacking skeletal muscle PGC-1α1. Finally, the research group measured PGC-1α1 in skeletal muscle of wild-type mice and of healthy adult humans before and after they took part in an exercise program and found that PGC-1α1 concentrations increased similarly in the two groups.

The results suggest that “exercised muscle acquires a detoxification role in stressful conditions,” Ruas told The Scientist, and highlight the potential benefit of physical exercise for people with depression.