exercising rats but also prevented the normal
increase in brain tryptophan level caused by
exhaustive exercise (T. Yamamoto, personal
communication). Calders et al.(1997) observed
an increase in the time to fatigue, as well as
an increase in plasma ammonia, in fasting rats
injected with 30 mg of branched-chain amino
acids 5 min before exercise, compared to those
injected with placebo.
The data in Table 11.2 indicate that admini-
stration of branched-chain amino acids alone
appears to have a more beneficial effect than
when added to carbohydrate. It also seems that
the higher the dose of branched-chain amino
acids, the more likely it is that plasma ammonia
levels will be elevated. This suggests that lower
doses are more likely to be beneficial. In the
majority of studies, the branched-chain amino
acids have been administered before exercise. It
may be that administration during exercise was
the reason that Blomstrand et al.(1997) and
Mittlemanet al.(1998) failed to observe a change
in plasma ammonia. Whether a bolus dose is
given or whether separate doses are given
during exercise could be important for the
release of ammonia from muscle.
In conclusion, beneficial effects of branched-
chain amino acids have been seen on aspects of
both mental and physical fatigue in exhaustive
exercise. Most studies have not investigated
effects on mental fatigue. However, the mental
exertion necessary to maintain a given power
output is an integral feature of central fatigue.
Cellular nutrition in the
immune system
For many years, it was thought that both
lymphocytes and macrophages obtained most
of their energy from the oxidation of glucose.
However, it has now been shown that these cells
also use glutamine and that its rate of utilization
is either similar to or greater than that of glucose.
There are clear lines of evidence which support
the view that glutamine is used at a very high
rate by lymphocytes and by macrophages in vivo.
1 The maximal catalytic activity of glutaminase,
the key enzyme in the glutamine utilization
pathway, is high in freshly isolated resting
lymphocytes and macrophages (Ardawi &
Newsholme 1983, 1985).
2 The rates of utilization of glutamine are
high: (i) in freshly isolated lymphocytes and
macrophages (Ardawi & Newsholme 1983,
1985) and (ii) in cultured lymphocytes and
macrophages, and in T- and B-lymphocyte-
derived cell lines (Ardawi & Newsholme 1983,
1985; Newsholme et al. 1988).
3 A high rate of glutamine utilization by lym-
phocytesin vitromaintains unusually high intra-
cellular concentrations of glutamine, glutamate,
aspartate and lactate. Very similar levels of these
intermediates are seen in intact lymph nodes
removed from anaesthetized rats and frozen
rapidly prior to extraction of the tissues (T. Piva
and E.A. Newsholme, unpublished data).
In addition, although various lymphocyte
subsets have not been studied, the available
evidence suggests that B- and T-lymphocytes
utilize glutamine at similar rates (Ardawi &
Newsholme 1983, 1985; Newsholme et al.1988).
Surprisingly, little of the carbon of glucose
(<10%) and only some of that of glutamine
(10–30%) is oxidized completely by these cells:
glucose is converted almost totally into lactate,
glutamine into glutamate, aspartate, alanine
and CO 2. The partial oxidation of these fuels is
known as glycolysis and glutaminolysis, respec-
tively. From these simple metabolic characteris-
tics several questions arise.
1 What is the significance of these high rates?
2 Why is the oxidation only partial?
3 What are the consequences for the whole
organism?
4 Does the plasma glutamine level ever decrease
sufficiently to decrease the rate of such utiliza-
tion by these cells, and hence decrease their
ability to respond to an immune challenge?
High rates of glycolysis and glutaminolysis
will provide energy for these cells. In addition,
glutamine provides nitrogen for synthesis of
several important compounds, e.g. purine and
pyrimidine nucleotides, which are needed for
the synthesis of new DNA and RNA during pro-