The symptoms of depression were reduced in mice models which had high levels of PGC-1a1 in their skeletal muscle.
Exercising, and the high levels of PGC-1a1 that can stem from exercise, can reduce the symptoms of depression, according to research published in Cell.
Researchers from the Karolinska Institute in Sweden studied animal models with genetically modified high levels of the protein PGC-1a1. It was previously understood that PGC-1a1 increases in skeletal muscle with physical activity.
The mice, which were compared against normal control mice, were put into a stressful environment comprised of loud noises, flashing lights, and reversed circadian rhythm at irregular intervals. They spent 5 weeks under the mild stress environment. The normal mice had developed depressive behavior and the genetically modified mice — those who had well trained muscle characteristics – showed no depressive symptoms.
“Our initial research hypothesis was that trained muscle would produce a substance with beneficial effects on the brain,” Jorge Ruas, PharmD, PhD, principal investigator of the study, said in a press release. “We actually found the opposite: well-trained muscle produces an enzyme that purges the body of harmful substances. So in this context the muscle’s function is reminiscent of that of the kidney or the liver.”
The mice with the high levels of PGC-1a1 also were discovered to have high levels of an enzyme called KAT, which is a convert substance typically formed during stress. KAT turns into kynurenic acid, which cannot pass from blood into the brain. Though researchers do not know the exact function of kynurenine, high levels can be observed in human patients with mental illness.
When the control group of mice was given kynurenine, they displayed depressive behavior. However, the genetically modified, PGC-1a1 increased mice did not show depressive symptoms when given kynurenine. The PGC-1a1 mice never showed elevated kynurenine levels in their blood, the researchers believe, because the KAT enzymes in their muscles moved quickly to convert it into kynurenic acid. The authors conclude this was a protective mechanism demonstrated by the PGC-1a1 mice.
“It’s possible that this work opens up a new pharmacological principle in the treatment of depression, where attempts could be made to influence skeletal muscle function instead of targeting the brain directly,” Ruas continued. “Skeletal muscle appears to have a detoxification effect that, when activated, can protect the brain from insults and related mental illness.”
In the future, the research team hopes to build on therapeutic methods by targeting the PGC-1a1 in skeletal muscle.
“In neurobiological terms, we actually still don't know what depression is,” Mia Lindskog, Karolinska Institute researcher continued. “Our study represents another piece in the puzzle, since we provide an explanation for the protective biochemical changes induced by physical exercise that prevent the brain from being damaged during stress.”