In
a study in the journal Cell, Jorge Ruas and Maria Lindskog show how physical
exercise protects the brain from stress-induced depression in mice.
Credit: Ulf Sirborn
Physical
exercise has many beneficial effects on human health, including the protection
from stress-induced depression. However, until now the mechanisms that mediate
this protective effect have been unknown. In a new study in mice, researchers
at Karolinska Institutet in Sweden show that exercise training induces changes
in skeletal muscle that can purge the blood of a substance that accumulates
during stress, and is harmful to the brain. The study is being published in the
journal Cell.
"In
neurobiological terms, we actually still don't know what depression is. 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," says Mia Lindskog,
researcher at the Department of Neuroscience at Karolinska Institutet.
It
was known that the protein PGC-1a1 (pronounced PGC-1alpha1) increases in
skeletal muscle with exercise, and mediates the beneficial muscle conditioning
in connection with physical activity. In this study researchers used a
genetically modified mouse with high levels of PGC-1a1 in skeletal muscle that
shows many characteristics of well-trained muscles (even without exercising).
These
mice, and normal control mice, were exposed to a stressful environment, such as
loud noises, flashing lights and reversed circadian rhythm at irregular
intervals. After five weeks of mild stress, normal mice had developed
depressive behaviour, whereas the genetically modified mice (with well-trained
muscle characteristics) had no depressive symptoms.
"Our
initial research hypothesis was that trained muscle would produce a substance
with beneficial effects on the brain. 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," says Jorge Ruas, principal investigator at the Department
of Physiology and Pharmacology, Karolinska Institutet.
The
researchers discovered that mice with higher levels of PGC-1a1 in muscle also
had higher levels of enzymes called KAT. KATs convert a substance formed during
stress (kynurenine) into kynurenic acid, a substance that is not able to pass
from the blood to the brain. The exact function of kynurenine is not known, but
high levels of kynurenine can be measured in patients with mental illness. In
this study, the researchers demonstrated that when normal mice were given
kynurenine, they displayed depressive behaviour, while mice with increased
levels of PGC-1a1 in muscle were not affected. In fact, these animals never
show elevated kynurenine levels in their blood since the KAT enzymes in their
well-trained muscles quickly convert it to kynurenic acid, resulting in a
protective mechanism.
"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. Skeletal muscle
appears to have a detoxification effect that, when activated, can protect the
brain from insults and related mental illness," says Jorge Ruas.
Depression
is a common psychiatric disorder worldwide. The World Health Organization (WHO)
estimates that more than 350 million people are affected.
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Journal Reference:
Leandro
Z. Agudelo, Teresa FemenÃa, Funda Orhan, Margareta Porsmyr-Palmertz, Michel
Goiny, Vicente Martinez-Redondo, Jorge C. Correia, Manizheh Izadi, Maria Bhat,
Ina Schuppe-Koistinen, Amanda Pettersson, Duarte M. S. Ferreira, Anna Krook,
Romain Barres, Juleen R. Zierath, Sophie Erhardt, Maria Lindskog, and Jorge L.
Ruas. Skeletal Muscle PGC-1a1 Modulates Kynurenine Metabolism and Mediates
Resilience to Stress-Induced Depression. Cell, September 2014
