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Old 01-14-2006, 10:27 AM
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By: Karl Hoffman at http://www.scivation.com/?pageID=26

Citrulline malate (CM) is a combination of two compounds that occur naturally in the human body. Malate is an intermediate in the so-called tricarboxylic acid cycle (TCA). ATP, which the body uses as a source of energy, is produced via the TCA when oxygen is abundant. (In reality, no ATP is produced directly from the TCA, although this statement is often heard. Rather, reduced coenzymes, NADH, are used to generate ATP in electron transport chain powered oxidative phosphorylation.) This is so called aerobic energy production.

Tricarboxylic acid cycle (TCA) at a glance. Each kind of major fuel is converted to acetyl groups, which are handled by attachment to a particular coenzyme known as coenzyme A. Ultimately ATP is produced from NADH generated by the TCA.

Malate is dehydrogenated in the TCA cycle to oxaloacetate, the concentration of which is one of the most critical controls of the rate of aerobic ATP production. During prolonged aerobic activity, and in patients suffering from malate deficiency, malate becomes depleted and the TCA is unable to produce ATP fast enough to meet the demands of working muscle. One classic disease characterized by malate deficiency is fibromyalgia. When patients suffering with this disease are given malate, their energy levels improve dramatically (1).

Not only patients suffering from malate deficiency benefit from malate supplementation. As mentioned above, strenuous, prolonged aerobic activity depletes the body’s malate stores. One recent study looked at the effects of CM supplementation in 18 otherwise healthy men who complained of easy fatigability. (2) The subjects were administered 6 gm/day of CM for 15 days. To quote from the results of the study,

"CM ingestion resulted in a significant reduction in the sensation of fatigue, a 34% increase in the rate of oxidative ATP production during exercise, and a 20% increase in the rate of phosphocreatine recovery after exercise, indicating a larger contribution of oxidative ATP synthesis to energy production… The expansion of the TCA intermediate pool [through malate supplementation] can therefore be regarded as a means of attaining higher rates of aerobic energy production, in agreement with our results showing that malate supplementation promotes a greater contribution of aerobic ATP production to total energy production. These results suggest that this hyperactivation of aerobic ATP production coupled to a reduction in anaerobic energy supply may contribute to the reduction in fatigue sensation reported by the subjects."So not only were objective measures of energy production increased, but the study participants felt a subjective improvement in energy levels as well.

Thus far we have only addressed the role of malate in enhancing ATP production during aerobic metabolism. What about citrulline? Citrulline is a non-essential amino acid produced from glutamine in the body. Citrulline is involved in the so-called urea cycle, which is responsible for the removal of excess nitrogen from the breakdown of amino acids. Were excessive levels of nitrogen to accumulate in the body, ammonia toxicity would develop. Besides stimulating hepatic ureogenesis , citrulline also promotes the renal reabsorption of bicarbonates. The latter acts as a buffer against lactic acidosis, which also helps to stave off fatigue. In fact there has been some debate over the years whether citrulline or malate is primarily responsible of prolonging endurance (3). The consensus now seems to be that the two compounds work in concert, with malate maintaining TCA intermediates and allowing for increased ATP production, and citrulline buffering against lactic acid and ammonia buildup.

So we have seen that citrulline malate seems to be a worthwhile adjunct to any supplement protocol, especially where aerobic performance and fatigue resistance are important.
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