to total energy expenditure decreases with in-
creasing exercise duration during prolonged
(>90 min) moderate-intensity (65% of V
.
o2max.)
exercise.
Factors limiting fat oxidation
by muscle
Factors limiting fatty acid uptake
by muscle cells
As previously discussed, the metabolism of FA
derived from adipose tissue lipolysis constitutes
a major substrate for oxidative metabolism, espe-
cially during prolonged, low-intensity exercise.
The metabolism of long-chain FA is a complex
and integrated process that involves a number of
events: FA mobilization from peripheral adipose
tissue, transport in the plasma, transport and
permeation across muscle cell membranes and
interstitium, cytoplasmic transport, and intracel-
lular metabolism. The first stage in this process,
the mobilization of lipids, plays a key role in the
subsequent regulation of FA utilization during
both the resting state and exercise.
During perfusion of the muscle capillaries, FA
bound to albumin or stored in the core of chy-
lomicrons and VLDL have to be released prior to
transport across the vascular membrane. In the
case of VLDL and chylomicrons, this is achieved
by the action of the enzyme lipoprotein lipase
(LPL). LPL is synthesized within the muscle
cell and, after an activation process, is translo-
cated to the vascular endothelial cell membrane
where it exerts its enzymatic action on TG.
LPL also expresses phospholipase A 2 activity
which is necessary for the breakdown of the
phospholipid surface layer of the chylomicrons
and lipoproteins.
LPL activity is upregulated by caffeine, cate-
cholamines and adrenocorticotrophic hormone
(ACTH), and downregulated by insulin (for
review, see Jeukendrup 1997). After TG hydroly-
sis, most of the FA will be taken up by muscle,
whereas glycerol will be taken away via the
bloodstream to the liver, where it may serve as
a gluconeogenic precursor. During the postab-
sorptive state, the concentration of circulating
TG in plasma is usually higher than that of FA, in
contrast to the fasting state when chylomicrons
are practically absent from the circulation.
Nevertheless, the quantitative contribution of
circulating TG to FA oxidation by the exercising
muscle cells in humans is somewhat uncertain.
Due to technical limitations, no reliable data are
available to determine whether FA derived from
the TG core of VLDL or chylomicrons sub-
stantially contribute to overall FA utilization.
However, it is interesting to note that even a
small extraction ratio of the order of 2–3% of
FA/TG could potentially cover over up to 50%
of total exogenous FA uptake and subsequent
oxidation (Havel et al. 1967).
The arterial concentration of FA strongly
affects FA uptake into muscle both at rest and
during low-intensity exercise (for review, see
Bulow 1988). This implies an FA gradient from
blood to muscle in these conditions, which is
achieved by a relatively rapid conversion of FA,
taken up by the muscle cell, to fatty acyl-CoA.
The rate of the latter reaction step is controlled by
fatty acyl-CoA synthetase. During transport of
FA from blood to muscle, several barriers may
limit FA uptake, including the membranes of the
vascular endothelial cell, the interstitial space
between endothelium and muscle cell, and
finally the muscle cell membrane (for review, see
van der Vusse & Reneman 1996).
Uptake by endothelial cells is most likely
protein mediated. Both albumin-binding protein
and membrane-associated FA-binding proteins
(FABP) may play a role. After uptake, most FAs
will diffuse from the luminal to the abluminal
membrane of the endothelial cells as free mole-
cules. Although small amounts of FABP are
present at this site, their role in transmembrane
FA transport is assumed to be unimportant. Once
in the interstitial space, albumin will bind the
FAs for transport to the muscle cell membrane.
Here the FAs are taken over by a fatty-acid-
transporting protein, or will cross the membrane
directly because of their lipophilic nature. In the
sarcoplasm, FABP, which is present in relatively
high concentrations, is crucial for FA transport to