New mechanism unveiled, linking sports to stress related depression.
Chronic stress (CS) is associated with the development of depression. Though the mechanisms are complex and still largely obscure, there is evidence that the general state of low-grade inflammation induced by Chronic stress plays a role in promoting depression.
Chronic stress in fact modulates the activity of the brain-centered HPA axis (hypothalamus-pituitary-adrenal axis) and the SAM peripheral system (sympathetic-adrenomedullary system) that regulate the release of inflammatory molecules. Increased levels of pro-inflammatory molecules in the brain can hinder synaptic plasticity and neuronal activity, and consequently alter the function of brain structures implicated in the control of emotions and behavior, ultimately contributing to the onset of depression.
It is known that physical exercise improves the symptoms of depression. Several hypotheses have been formulated to explain how this occurs, but no clear biochemical mechanism had so far been demonstrated.
A paper recently published in Cell by Agudelo and colleagues from the Karolinska Institute in Stockholm, identifies a molecular pathway that links skeletal muscle activity during training to protective effects in the brain that can prevent or alleviate depression in individuals sustaining chronic psychosocial stress.
The scientists concentrated on a protein called PGC-1a1 that is produced in skeletal muscles during physical exercise. Interestingly, mice that have higher than normal levels of PGC-1a1 in skeletal muscles (PGC-mice) present constitutive features normally induced by endurance training, like lean body and resistance to fatigue and to muscle atrophy.
It is known that mice respond to chronic mild stress by developing a depressive-like behavior. The researchers showed that, as expected, mild stressors (like loud noise, restraint, wet cages, stroboscopic illumination etc.) applied for several weeks to control mice at unpredictable times decreased animals’ activity as measured in specific tests, as well as their consumption of sugar, which are two hallmarks of depressive behavior.
In accordance with these observations, the brains of these mice also contained decreased levels of neurotrophic factors and of proteins involved in neuronal transmission and synaptic plasticity, therefore providing a biological readout of the impact of chronic stress on brain function.
By contrast, PGC-mice under the same stress conditions did not present any depressive symptoms or alterations in neuronal transmission.
Avoiding the brain
How does elevated PGC-1a1 in skeletal muscles counteract the effects of chronic stress on the brain?
The scientists demonstrated that PGC-1a1 regulates a metabolic pathway that controls the degradation of the amino acid tryptophan. In particular, chronic stress and conditions that in general promote inflammation induce the conversion of tryptophan to a molecule called kynurenine (KYN). KYN enters the blood circulation and reaches the brain, where it is further metabolized in compounds that promote neuroinflammation and hamper synaptic remodeling and neural transmission.
Agudelo and colleagues demonstrated that high levels of muscle PGC1a1 oppose these effects by transforming KYN into another metabolite, called kynurenic acid (KYNA). Also KYNA circulates in the blood but, differently from KYN, it cannot cross the blood brain barrier and thus cannot reach the brain. Hence, by decreasing peripheral KYN levels, and as a consequence the possibility of generating toxic metabolites in the brain, muscle PGC1a1 prevents brain damages that would promote depression.
Is this mechanism operative also in humans?
The researchers found a significant increase in PGC1a1 concentration and activity in the skeletal muscles of volunteers after three weeks of intense physical training. Accordingly, KYNA levels are high in the blood of individuals after endurance training, supporting the idea that elevated levels of muscle PGC1a1 would shift tryptophan metabolism to KYNA production and induce brain protection.
Even if the effects of this pathway in chronically stressed and depressed subjects were not measured in this study, the results described have meaningful implications.
From the therapeutic perspective, the identification of a specific molecular pathway that links skeletal muscle activity to promotion of brain health suggests that drugs that reduce plasma levels of KYN can mimic the effects of physical training in depressed individuals who are usually reluctant to carry out regular physical exercise.
It is also worth noting that PGC was already implicated in brain protection as an inducer of the neurotrophic factor BDNF, as written in this post, but now Agudelo and colleagues found that this mechanism is not activated in PGC-mice, and probably is not a significant factor in opposing chronic stress-induced depression. This observation thus opens the question of whether the mechanism described by Agudelo and its therapeutic implications are valid also in other forms of depression that are not related to stress.
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 (2014). Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression. Cell, 159 (1), 33-45 PMID: 25259918
Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, & Spiegelman BM (2013). Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell metabolism, 18 (5), 649-59 PMID: 24120943
physical training, exercise, sports, stress, depression, chronic stress, pgc, kyn, kyna