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JAMA 1984; 252: 1443 Fatigue During Prolonged Exercise The cause ( s) of fatigue during prolonged submaximumexercise has been a researchinterest of exercisescientists for over half a century.Christensen and Hansen ’ were among the first to report that increasing the carbohydratecontent of the diet improved endurance capacity during prolonged cycling. In the early l!XOs, the rein& duction of a percutaneousneedle biopsy technique provided the meansby which we could study metabolic eventsin muscleduring exercisein general and the influence of diet on exercise capacity in particular. 23 Subsequent studies confirmed a strong association between the depletion of muscle glycogen stores and the onset of fatigue. More recent studieshave also confirmed that during pm- longed running glycogen depletion occursin both type I and type II muscle? During very heavy exercisethat lasts severalminutes rather than hours, fatigue is associated not with glycogen depletion but with the accumulation of glycolytic metabolites, of which hydro- gen ions are the most prominent? Ingesting a carbohydrate solution during prolonged submaximal exercise delays the onsetof fatigue6 and improvesendurance perfor- mance.’ The mechanism(s) responsible for the improvement in endurance capacityis linked to glycogen sparing during exercise’ as a consequence of the metabolism of the exogenous supply of carbohydrate. Although most attention has been given to metabolic events in skeletal muscle, there is an increasingamount of interest in changesin brain biochemistry and their link with fatigue. The central fatigue hypothesis suggests a link between plasma tryptophan, a precumor of the neuro-transmitter 5hydmxytrypta- mine (serotonin), and a disinclination for spontaneous activity.’ Tryptophan binds to the same sites on plasma albumin as fatty acids, and so when the concentration of plasma fatty acids are low, then the amount of free hyptophan is low. However, during prolonged exercise there is an increase in the concentration of plasma fatty acids,and so tryptophan is displacedand the amount of free tryptophan available for transport across the blood-brain banier increases, leading to a rise in the concentrationof semtonin. Some studies suggest that the delay in the onset of fatigue, when a glucose solution is ingested during exercise, may be a consequence of glucose-induced decreased plasma fatty acids and, therefore, in free tryptophan concentration.‘o The carriermechanismresponsible for the translocation of tryptophan is competitively shared with large neutralamino acids, which includes the branchedchain amino acids (BCAA). Increasing the plasma BCAA concentration has been proposed as a method of reducing tryptophan transport into the brain, thus reducing the potential large increasein serotonin concentration. In this issue of Nutition, ” this potential nutritional method of delaying the onset of fatigue is described in a study on the influence of ingestinga solution of branched-chain amino acids on plasmaand muscle concentrations of amino acids during prolonged submaximal exercise. The authorsreport, however, that there was no difference in the maximum amount of work their subjects could perform during a 20-min period of all out exerciseimmediately after an hour of submaximal cycling. In the same study, but reported else-