The activity of muscle hexokinase is sufficient, in principle, for all the energy for sustained aerobic exercise to be derived from uptake of plasma glucose. In fact, as we have seen, this would reduce the length of time during which the exercise can be sustained at the highest rate. Simultaneous oxidation of glucose and fatty acids therefore produces the longest possible period of sustained high intensity exercise. The availability of fatty acids to the muscles also reduces the rate of glucose oxidation, by operation of the glucose-fatty acid cycle (see Section 188.8.131.52). There is experimental evidence that increasing the availability of fatty acids leads to sparing of glycogen, thus at least in principle allowing high-intensity exercise to be continued for longer.3
The fatty acids oxidised during endurance exercise come from two main sources: triacylglycerol stored in adipose tissue, and triacylglycerol stored in the muscles themselves. The latter is difficult to study and the factors controlling muscle triacylglycerol utilisation are not clear. Nevertheless, the muscle triacylglycerol concentration falls during intense, long-lasting exercise. The regulation of fat mobilisation from adipose tissue is better understood. The main stimulus for this to increase during exercise is adrenergic. Blockade of P-adrenergic receptors in adipose tissue with the drug propranolol prevents the increase in lipolysis during exercise (see Fig. 7.7). The main stimulus may be circulating adrenaline or activation of the sympathetic nerves. Studies of exercise in people who have had spinal cord injuries, so that some of their adipose tissue is innervated whilst some is not, suggest that circulating adrenaline is more important than the sympathetic innervation. The adrenergic stimulation of lipolysis may be reinforced by the slight fall in insulin concentration (thus relieving the normal suppression of lipolysis by insulin). In sustained exercise (longer than, say, 30- 60 min) then the increases in plasma growth hormone and cortisol concentrations (Fig. 8.12) may potentiate the adrenergic stimulation of lipolysis, perhaps by an increase in the amount of enzyme (hormonesensitive lipase) present.
The fatty acids liberated in adipose tissue must be transported through the plasma bound to albumin to the muscles for uptake and oxidation. It may be a step in this pathway which limits the rate at which fatty acids can be oxidised, leading to the restriction of the contribution of fatty acid oxidation to about 60% of the maximal sustainable rate of energy expenditure. The evidence, from experiments in which the availability of fatty acids in the plasma is increased by the means described earlier, suggests the following. In moderate-intensity exercise, up to about 65% of the maximal aerobic power, increased availability of fatty acids increases the rate of fat oxidation, implying that the normal limitation on their oxidation is at the level of release from adipose tissue. However, in higher intensity exercise (an elite marathon runner maintains 80-85% of maximal aerobic power) then increased availability of fatty acids leads to very little increase in fat oxidation: it appears that the rate of fatty acid utilisation by muscle is limited.
There is some information as to why these steps may be limiting. The release of non-esterified fatty acids into the plasma depends upon the availability of albumin. If the blood flow through adipose tissue is restricted, there may be insufficient albumin available to carry away all the fatty acids formed in lipoly-sis. Non-esterified fatty acids may then accumulate in the tissue, as described in the case of physical trauma (Section 184.108.40.206 and Table 7.1). To some extent this may cause an increase in their re-esterification to form triacylglycerol, but it also appears that they accumulate as such. When exercise stops, there is often a sudden release of fatty acids into the general circulation not accompanied by the expected one mole of glycerol for each three moles of fatty acids. It is not, perhaps, surprising that blood flow through adipose tissue should be restricted. We have already seen that a high sympathetic activity or circulating adrenaline concentration can restrict blood flow through many tissues by a-adrenergic effects on the blood vessels, and during exercise this occurs as part of the redistribution of blood to the working muscles. Adipose tissue is affected in just this way.
At higher intensities of exercise, the muscles appear unable to oxidise more fatty acids even if they are available in the plasma. The reason may be this. Glucose metabolism in muscle proceeds at a high rate during intense aerobic exercise. Acetyl-CoA is produced, via the action of pyruvate dehydrogenase, but will primarily be oxidised in the tricarboxylic acid cycle. However, the high concentration may cause some increase in flux through the first part of the pathway of de novo lipogenesis, thus increasing the concentration of the next intermediate in that pathway, malonyl-CoA (see Box 4.3). (Fatty acid synthase is not expressed in muscle.) As was discussed in Section 220.127.116.11, malonyl-CoA inhibits the entry of fatty acids into the mitochondrion for oxidation. Thus, glucose oxidation proceeding at a high rate may limit the muscles' ability to oxidise fat.
Thus, fat metabolism during high-intensity endurance exercise does not follow the rules we might expect on the basis of everything we know about human metabolism. The contribution of fatty acids is limited and the availability of glycogen limits the time for which high-intensity exercise can be maintained. We may speculate that perhaps the ability to run at high intensity for long periods was not important in terms of the evolution of Homo sapiens. Maybe the ability to sprint, to escape from a predator, was more important.
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