glycogen is available and the muscle pyruvate
concentration is kept high (Fig. 9.3). However, as
activation of the BCKADH complex is highest in
glycogen-depleted muscle (Van Hall et al. 1996),
this mechanism eventually is expected to lead to
a decrease in the concentration of TCA-cycle
intermediates. This again may lead to a reduction
of the TCA-cycle activity, inadequate adenosine
triphosphate turnover rates and, via increases in
the known cellular mediators, to muscle fatigue
(Fitts 1994).
BCAA supplementation and performance
After oral ingestion, BCAA escape from hepatic
uptake and are rapidly extracted by the leg
muscles (Aoki et al. 1981; MacLean et al. 1996; Van
Hallet al. 1996) and this is accompanied by
activation of the BCKADH complex at rest and
increased activation during exercise (Van Hall
et al. 1996). This could imply that the indicated
carbon drain on the TCA cycle is larger after
BCAA ingestion and that BCAA ingestion by this
mechanism leads to premature fatigue during
prolonged exercise, leading to glycogen deple-
tion. Evidence in support of this hypothesis
has been obtained (Wagenmakers et al. 1990) in
patients with McArdle’s disease, who have no
access to muscle glycogen due to glycogen
phosphorylase deficiency and therefore can
be regarded as an ‘experiment of nature’ from
which we can learn what happens during
exercise with glycogen-depleted muscles. BCAA
supplementation increased heart rate and led to
premature fatigue during incremental exercise
in these patients. This may contain the message
that BCAA supplementation has a negative effect
on performance by the proposed mechanism
in healthy subjects in conditions where the
glycogen stores have been completely emptied
by highly demanding endurance exercise.
However, with coingestion of carbohydrate,
BCAA ingestion did not change time to exhaus-
tion in healthy subjects (Blomstrand et al. 1995;
Van Hall et al. 1995a; Madsen et al. 1996). As
BCAA ingestion increases ammonia production
by the muscle and plasma ammonia concentra-
tion during exercise (Wagenmakers 1992; Van
Hallet al. 1995a, 1996; MacLean et al. 1996;
Madsenet al. 1996), and as ammonia has been
suggested to lead to central fatigue and loss of
motor coordination (Banister & Cameron 1990),
great care seems to be indicated with the use of
BCAA supplements during exercise, especially
in sports that critically depend on motor coordi-
nation. The hypothesis of Newsholme and col-
leagues (see Chapter 11 for details) (Blomstrand
et al. 1991) that BCAA supplements improve
endurance performance via a reduction of
central fatigue by serotoninergic mechanisms
has not been confirmed in recent controlled
studies (Blomstrand et al. 1995; Van Hall et al.
1995a; Madsen et al. 1996).Importance of TCA-cycle anaplerosis for
the maximal rate of substrate oxidation
during exercise
Muscle glycogen is the primary fuel during pro-
longed high-intensity exercise such as practised
by elite marathon runners. High running speeds
(≥20 km · h–1) are maintained by these athletes for
periods of 2 h. However, they have to reduce the
pace when the muscle glycogen concentration is
falling and glycolytic rates cannot be maintained.
This either indicates that there is a limit in the
maximal rate at which fatty acids can be mobi-
lized from adipose tissue and intramuscular
stores and oxidized or that there is a limitation in
the maximal rate of the TCA cycle when gly-
colytic rates are falling as a consequence of
glycogen depletion. It is proposed here that
the decrease in muscle pyruvate concentration
which occurs when the glycogen stores are
reduced leads to a decrease of the anaplerotic
capacity of the alanine aminotransferase reaction
and thus leads to a decrease in the concentration
of TCA-cycle intermediates (due to insufficient
counterbalance of the carbon-draining effect of
the BCAA aminotransferase reaction). This again
will lead to a reduction of TCA-cycle activity and
the need to reduce the pace (fatigue). The follow-
ing observation seems to support this hypo-
thesis. Patients with McArdle’s disease cannot