Central
Fatigue
Lecture 18 Part I
Define fatigue.
operating definition: inability to
maintain a desired level of intensity.
We usually think of fatigue during exercise as
occurring in the muscle; e.g. glycogen depletion or
some other limitation decreasing the ability to
produce ATP at the necessary rate.
Some work suggests other factors are involved.
Coyle et al. infused glucose into the blood of trained
cyclists (to make sure they were never limited by
availability of carbohydrate) and, though they were
never depleted, they fatigued and stopped cycling.
In 1987, Newsholme et al. proposed a novel
idea called the “central fatigue hypothesis”.
The basis for the idea is that fatigue during
endurance exercise is related to a buildup
of serotonin (a neurotransmitter) in the brain.
In 1987, Newsholme et al. proposed a novel
idea called the “central fatigue hypothesis”.
The basis for the idea is that fatigue during
endurance exercise is related to a buildup
of serotonin (a neurotransmitter) in the brain.
It is true that increased levels of serotonin causes
drowsiness and fatigue (many sleeping aids work by
raising levels of serotonin in the brain).
Tryptophan is an amino acid
that is converted to 5OH tryptamine and then
to serotonin in the brain.
In order to get into the
brain, tryptyophan must Blood Vessel
cross the blood-brain
barrier via a transporter.
Brain
The transporter is not
specific for tryptophan,
it also transports
branched chain amino
acids (BCAA),
so there is a
“competition”
for transport.
Transporter
During exercise, BCAA’s are taken up by muscle
and oxidized for energy.
Late in exercise, when muscle glycogen stores are
low, this process is accelerated. Greater uptake of
BCAAs late in exercise leads to lower blood BCAA
levels and increased ratio of tryptophan/BCAA.
So more tryptophan gets into the brain
= more serotonin production.
In addition, as exercise progresses, more free fatty
acids (FFA) are liberated from triglyceride stores
and blood level of FFA goes up.
FFA’s and tryptophan are both
transported in the blood by
albumen (a common plasma protein).
As level of FFA’s goes up, more tryptophan is
displaced from binding sites on albumen and the
“free” tryptophan concentration rises.
So, increased BCAA uptake by muscle AND
decreased binding capacity by albumen greatly
enhances the transport of tryptophan into the brain
Hypothesis: increased tryptophan into brain = more
serotonin = central fatigue = stop exercise.
FFA
FFA
tryptophan
albumen
FFA
BCAA
How do you test the central fatigue hypothesis?
What things do you need to know?
1. Does the ratio of tryptophan/BCAA in the blood
increase during exercise?
2. Is there increased entry of tryptophan into the
brain?
3. Does it cause more production of serotonin?
4. Does that change in serotonin cause more
fatigue?
Because supplement industry is driven
by business and not scientific motives,
the FIRST studies actually done tested
the effects of supplements on humans.
A rational approach would have been
to supplement with tryptophan and see if it caused
MORE fatigue. But, b/c you can’t make money from
an ergolytic (inhibiting performance) compound, the
first studies tested the efficacy of BCAA supplements
to delay “time to fatigue” in athletes.
Complications: “time to fatigue” is easy to measure
in theory but hard to interpret.
In mid-90’s, dozens of studies looking at effects of
BCAA (with and w/o CHO) on performance. Most
showed no effect. Some improved performance but
studies were usually seriously flawed.
e.g., Blomstrand et al. in 1991 studied effects of
BCAA ingestion vs. flavored water on marathon
runners. No effects unless divided group into “fast”
and “slow”, saw improvement in the “slow” runners.
Flaws:
1. subjects in 2 groups not matched
2. did not control energy or CHO intake
3. division of runners arbitrary
Finally, in about 2003, a group of investigators
infused tryptophan into the bloodstream of rodents
and looked at the uptake into the brain and time to
exhaustion. They found that the greatly elevated
levels of tryptophan in the blood did change the
BCAA/tryptophan ratio but had no effect at all on
endurance.
Bottom line: the evidence to suggest BCAA
supplements improve endurance performance is
almost non-existent. The best designed studies all
show negative results.