Metabolism of Branched-Chain Amino Acids and Ammonia During Exercise: Clues from McArdle's Disease*

Abstract

Patients with McArdle's disease (myophosphorylase deficiency) cannot use muscle glycogen as an energy source during exercise. They therefore are an ideal model to learn about the metabolic adaptations which develop during endurance exercise leading to glycogen depletion. This review summarizes the current knowledge of ammonia and amino acid metabolism in these patients and also adds several new data. During incremental exercise tests in patients with McArdle's disease, forearm venous plasma ammonia concentration rises to a value between 200 and 500 microM. Femoral arteriovenous difference studies show that muscle produces the ammonia. The leg release of both ammonia and glutamine (in mumol/min) has been estimated to be five- to tenfold larger in one of these patients than in healthy individuals exercising at comparable relative work load. Patients with McArdle's disease have a larger uptake of branched-chain amino acids (BCAA) by exercising leg muscles and show a more rapid activation of the muscle branched-chain 2-oxo acid dehydrogenase complex, a key enzyme in the degradation of the BCAA. In general, supplements of BCAA taken before the exercise test lead to a deterioration of exercise performance and a higher increase in heart rate and plasma ammonia during exercise, whereas supplements of branched-chain 2-oxo acids improve exercise performance and lead to a smaller increase in heart rate and plasma ammonia. At constant power output, patients with McArdle's disease show a rapid increase in heart rate and exertion perceived in the exercising muscles, which peak within 10 min after the start of exercise and then fall again ("second wind"). Peak heart rate and peak exertion coincide with a peak in plasma ammonia. Ammonia production during exercise in these patients is estimated to exceed the reported breakdown of ATP to IMP and therefore most likely originates from the metabolism of amino acids. Deamination of amino acids via the reactions of the purine nucleotide cycle and glutamate dehydrogenase are possible pathways. Deamination of glutamine, released by muscle, by glutaminase present in the endothelial cells of the vascular system may also contribute to the ammonia production. The observations made in these patients have led to the hypothesis that excessive acceleration of the metabolism of BCAA drains 2-oxoglutarate in the primary aminotransferase reaction and thus reduces flux in the citric acid cycle and impedes aerobic oxidation of glucose and fatty acids. This draining effect is normally counteracted by the anaplerotic conversion of muscle glycogen to citric acid cycle intermediates, a reaction which is severely hampered in these patients due to the glycogen breakdown defect.(ABSTRACT TRUNCATED AT 400 WORDS)

Dissociation between muscle tricarboxylic acid cycle pool size and aerobic energy provision during prolonged exercise in humans

“…It was further suggested that a decrease in muscle [TCAI] during prolonged exercise -secondary to a reduction in muscle glycogen availability -compromises TCA cycle flux and hastens the onset of local muscle fatigue (Sahlin et al 1990;Wagenmakers et al 1990). These claims remain prevalent in the literature (e.g.…”

“…In 1990, two groups of investigators independently proposed that an increase in [TCAI] is necessary in order to attain high rates of aerobic energy provision, presumably by activating various near-equilibrium reactions in the TCA cycle (Sahlin et al 1990;Wagenmakers et al 1990). It was further suggested that a decrease in muscle [TCAI] during prolonged exercise -secondary to a reduction in muscle glycogen availability -compromises TCA cycle flux and hastens the onset of local muscle fatigue (Sahlin et al 1990;Wagenmakers et al 1990).…”

Protein and Amino Acid Needs of the Strength Athlete

“…It is likely that the exercise-induced increased leucine oxidation is related to the activation of branched-chain keto acid dehydrogenase (linuting enzyme in the leucine oxidation pathway) by exercise intensity and/or duration (58,59,89). Further, the observed increases during endurance exercise are greater in humans than in rodents (52), perhaps due to greater muscle dehydrogenase activity (61).…”

Administration of Tomato Juice or Aqueous Components of Tomato Reduces Fatigue Induced by Acute Treadmill Exercise

“…A mixture of amino acids-especially EAAs-is known to reduce fatigue, with BCAAs contributing significantly to this phenomenon. During endurance exercise, BCAAs act as a major energy source after the depletion of carbohydrates, and increased oxidation of BCAAs triggers a gradual decrease in tricarboxylic acid cycle intermediates, resulting in fatigue [19] [20]. BCAAs are also thought to influence central fatigue, which may be me- diated by 5-HT.…”