Mechanism: How Depression could be Controlled Through Physical Exercise

Physical exercise has many valuable outcomes on individual health, which includes the protection from stress-stimulated depression. However, till now the mechanisms that mediate this protective effect have been unidentified. In a new research in mice, scientists at Karolinska Institute show that physical exercise training causes modifications in skeletal muscle that can remove the blood of a substance that accumulates while in stress, and is dangerous to the brain. The research is being presented in the journal Cell.

“In neurobiological words, we basically still do not know what depression is. Our research shows one more piece in the puzzle, since we offer an clarification for the protective biochemical modifications stimulated by physical exercise that avoid the brain from being harmed while in stress,” states Mia Lindskog, investigator at the Department of Neuroscience at Karolinska Institutet.

It was identified that the protein PGC-1a1 (pronounced PGC-1alpha1) raises in skeletal muscle with physical exercise, and mediates the valuable muscle conditioning in relationship with physical exercise. In this research investigators applied a genetically modified mouse with higher levels of PGC-1a1 in skeletal muscle that reveals many features of well-trained muscles (even without exercising).

These mice, and usual control mice, were subjected to a stressful atmosphere, just like loud noises, blinking lights and reversed circadian rhythm at abnormal intervals. After 5 weeks of mild stress, regular mice had developed depressive behavior, while the genetically modified mice had no depressive symptoms.

“Our preliminary research hypothesis was that trained muscle would generate a substance with valuable effects on the brain. We basically identified the opposite: well-trained muscle generates an enzyme that purges the body of damaging substances. So in this perspective the muscle’s functionality is similar of that of the kidney or the liver,” states Jorge Ruas, principal investigator, Karolinska Institutet.

The scientists identified that mice with greater levels of PGC-1a1 in muscle also had greater levels of enzymes known as KAT. KATs convert a material formed during stress (kynurenine) into kynurenic acid, a chemical that is not capable to pass from the blood to the brain. The actual function of kynurenine is not identified, but high levels of kynurenine can be assessed in sufferers with mental sickness. In this research, the investigators exhibited that when regular mice were given kynurenine, they shown depressive behavior, while mice with enhanced levels of PGC-1a1 in muscle were not impacted. In fact, these animals never show raised kynurenine levels in their blood since the KAT enzymes in their well-trained muscles rapidly convert it to kynurenic acid, causing in a protective mechanism.

“It’s feasible that this work reveals a new pharmacological principle in the therapy of depression, where efforts could be made to impact skeletal muscle function rather of targeting the brain straight. Skeletal muscle seems to be to have a detoxification effect that, when triggered, can secure the brain from insults and related mental illness,” states Jorge Ruas.