NUTRITION IN SPORT

ferase reaction towards a new equilibrium with
production of a-ketoglutarate and alanine from
pyruvate (continuously supplied by glycolysis)
and glutamate (falling in concentration). Felig
and Wahren (1971) have shown that the rate of
release of alanine from muscle depended on the
exercise intensity (see also Eriksson et al. 1985)
and suggested a direct relation between the rate
of formation of pyruvate from glucose and the
rate of alanine release. This led to the suggestion
that the glucose–alanine cycle also operated
during exercise: glucose taken up by muscle
from the blood is converted via glycolysis to
pyruvate and then via transamination to alanine
to subsequently serve as substrate for gluconeo-
genesis in the liver and to help maintain blood
glucose concentration during exercise. Here we
propose that the alanine aminotransferase reac-
tion primarily functions for de novosynthesis of
a-ketoglutarate and TCA-cycle intermediates at
the start of exercise. The augmented glycolysis
during exercise thus appears to serve a dual
function (Fig. 9.3). More pyruvate is generated to
function (i) as a substrate for pyruvate dehydro-
genase and subsequent oxidation and (ii) to force
the alanine aminotransferase reaction towards
production of a-ketoglutarate and TCA-cycle
intermediates and thus to increase TCA-cycle
activity and the capacity to oxidize acetyl-CoA
derived from pyruvate and fatty acid oxidation.

Carbon drain of the BCAA aminotransferase
reaction in glycogen-depleted muscles:
its potential role in fatigue mechanisms

After the early increase in the concentration of
TCA-cycle intermediates during exercise, Sahlin
et al. (1990) observed a subsequent gradual
decrease in human subjects exercising until
exhaustion at 75% V

.
o2max.. We (Wagenmakers
et al. 1990, 1991; Van Hall et al. 1995b, 1996;
Wagenmakers & Van Hall 1996) have hypothe-
sized that the increased oxidation of the BCAA
plays an important role in that subsequent
decrease. The branched-chain a-keto acid dehy-
drogenase (BCKADH; the enzyme catalysing the
rate determining step in the oxidation of BCAA

126 nutrition and exercise

in muscle) is increasingly activated during pro-

longed exercise leading to glycogen depletion

(Wagenmakers et al. 1991; Van Hall et al. 1996).

After prolonged exercise, the muscle also begins

to extract BCAA from the circulation in gradually

increasing amounts (Ahlborg et al. 1974; Van Hall

et al. 1995b, 1996). Ahlborg et al. (1974) suggested

that these BCAA were released from the splanch-

nic bed. An increase in oxidation of the BCAA

by definition will increase the flux through the

BCAA aminotransferase step. In the case of

leucine this reaction will put a net carbon drain

on the TCA cycle as the carbon skeleton of

leucine is oxidized to three acetyl-CoA mole-

cules and the aminotransferase step uses a-

ketoglutarate as the amino group acceptor (Fig.

9.4). Increased oxidation of valine and isoleucine

will not lead to net removal of TCA-cycle inter-

mediates as the carbon skeleton of valine is oxi-

dized to succinyl-CoA and that of isoleucine

to both succinyl-CoA and acetyl-CoA (Fig. 9.1).

Net removal of a-ketoglutarate via leucine

transamination (Fig. 9.4) can be compensated for

by regeneration of a-ketoglutarate in the alanine

aminotransferase reaction as long as muscle

Fatty acids

Acetyl-CoA

Reduced

TCA cycle

activity

Glutamate

Leucine

α-KIC

3 Acetyl-CoA

α-ketoglutarate

Fig. 9.4Increased rates of leucine transamination

remove a-ketoglutarate from the tricarboxylic acid

(TCA) cycle during prolonged exercise. The

subsequent decrease in TCA-cycle flux limits the

maximal rate of fat oxidation in glycogen-depleted

muscles.a-KIC,a-ketoisocaproate.