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Phys Ed
How Exercise May Protect Against Depression
By Gretchen Reynolds
October 1, 2014 12:01 am October 1, 2014 12:01 am
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Credit Getty Images
Phys Ed
Phys Ed
Gretchen Reynolds on the science of fitness.
Exercise may help to safeguard the mind against depression through previously un
known effects on working muscles, according to a new study involving mice. The f
indings may have broad implications for anyone whose stress levels threaten to b
ecome emotionally overwhelming.
Mental health experts have long been aware that even mild, repeated stress can c
ontribute to the development of depression and other mood disorders in animals a
nd people.
Scientists have also known that exercise seems to cushion against depression. Wo
rking out somehow makes people and animals emotionally resilient, studies have s
hown.
But precisely how exercise, a physical activity, can lessen someones risk for dep
ression, a mood state, has been mysterious.
So for the new study, which was published last week in Cell, researchers at the
Karolinska Institute in Stockholm delved into the brains and behavior of mice in
an intricate and novel fashion.
Mouse emotions are, of course, opaque to us. We cant ask mice if they are feeling
cheerful or full of woe. Instead, researchers have delineated certain behaviors
that indicate depression in mice. If animals lose weight, stop seeking out a su
gar solution when its available because, presumably, they no longer experience no
rmal pleasures or give up trying to escape from a cold-water maze and just freez
e in place, they are categorized as depressed.
And in the new experiment, after five weeks of frequent but intermittent, low-le
vel stress, such as being restrained or lightly shocked, mice displayed exactly
those behaviors. They became depressed.
The scientists could then have tested whether exercise blunts the risk of develo
ping depression after stress by having mice run first. But, frankly, from earlie
r research, they knew it would. They wanted to parse how.
So they bred pre-exercised mice.
A wealth of earlier research by these scientists and others had shown that aerob
ic exercise, in both mice and people, increases the production within muscles of
an enzyme called PGC-1alpha. In particular, exercise raises levels of a specifi
c subtype of the enzyme known unimaginatively as PGC-1alpha1. The Karolinska sci
entists suspected that this enzyme somehow creates conditions within the body th

at protect the brain against depression.

But to determine if that theory was true, they had to isolate the PGC-1alpha1 fr
om all the other substances pumped out by the muscles during and after exercise.
So they created mice that, even without exercising, were awash in high levels o
f PGC-1alpha1. Their muscles produced lots of it, even when they were lazing aro
und.
The scientists then exposed these animals to five weeks of mild stress. The mice
responded with slight symptoms of worry. They lost weight. But they did not dev
elop full-blown rodent depression. They continued to seek out sugar and fought t
o get out of the cold-water maze. Their high levels of PGC-1alpha1 appeared to r
ender them depression-resistant.
But the scientists knew that the PGC-1alpha1 was almost certainly not directly p
rotecting the animals brains. It doesnt work that way, acting directly on cells. R
ather it is whats known as a promoter, sparking activity in genes, which in turn
express proteins that then affect various physiological processes throughout the
body.
So the scientists looked for which processes were being most notably intensified
in their PGC-1alpha1-rich mice. They found one in particular, involving a subst
ance called kynurenine that accumulates in human and animal bloodstreams after s
tress. Kynurenine can pass the blood-brain barrier and, in animal studies, has b
een shown to cause damaging inflammation in the brain, leading, it is thought, t
o depression.
But in the mice with high levels of PGC-1alpha1, the kynurenine produced by stre
ss was set upon almost immediately by another protein expressed in response to s
ignals from the PGC-1alpha1. This protein changed the kynurenine, breaking it in
to its component parts, which, interestingly, could not pass the blood-brain bar
rier. In effect, the extra PGC-1alpha1 had called up guards that defused the thr
eat to the animals brains and mood from frequent stress.
Finally, to ensure that these findings are relevant to people, the researchers h
ad a group of adult volunteers complete three weeks of frequent endurance traini
ng, consisting of 40 to 50 minutes of moderate cycling or jogging. The scientist
s conducted muscle biopsies before and after the program and found that by the e
nd of the three weeks, the volunteers muscle cells contained substantially more P
GC-1alpha1 and the substance that breaks down kynurenine than at the studys start
.
The upshot of these results, in the simplest terms, is that you reduce the risk o
f getting depression when you exercise, said Maria Lindskog, a researcher in the
department of neuroscience at the Karolinska Institute and a study co-author.
Whether the same biochemical processes likewise combat depression that already e
xists is less certain, said Jorge Ruas, a principal investigator at the Karolins
ka Institute and the studys senior author. But he is hopeful. We think that this m
echanism would be efficient if activated after depression has begun, he said. He
and his colleagues hoped to test that possibility in mice soon.
In the meantime, if work and other pressures mount, it may be a good idea to go
for a jog. It may just keep your kynurenine in check.
Fitness, Phys Ed, Depression (Mental), Exercise, Mental Health and Disorders
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