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.
The Role of Branch-Chain Amino Acids in Fatigue Resistance
The branched-chain amino acids isoleucine, leucine, and valine are widely used among athletes for their protein sparing effect.
L-leucine is also known as 2-amino-4-methylvaleric acid, alpha-aminoisocaproic acid and (S)-2-amino-4-methylpentanoic acid. It is abbreviated as Leu or by its one letter abbreviation L. Its molecular formula is C6H13NO2, and its molecular weight is 131.17 daltons.
L-isoleucine is also known as 2-amino-3-methylvaleric acid, alpha-amino-beta-methylvaleric acid and (2S, 3S)-2-amino-3-methylpentanoic acid. It is abbreviated as Ile or by its one letter abbreviation I. Its molecular formula is C 6H13NO2, and its molecular weight is 131.17 daltons.
L-valine is also known as 2-aminoisovaleric acid, 2-amino-3-methylbutyric acid, alpha-aminoisovaleric acid and (S)-2-amino-3-methylbutanoic acid. It is abbreviated as Val, and its one letter abbreviation is V. Its molecular formula is C5H11NO2, and its molecular weight is 117.15 daltons.
A number of studies have shown that branched chain amino acids exert both an anabolic and ergogenic effect.
For example, one study showed that BCAA administration post exercise resulted in an approximately 30% decrease amino acid efflux from skeletal muscle. The authors concluded that BCAAs exert a post training protein-sparing effect on muscle tissue (4). These results have been verified in numerous other studies. It is now believed that BCAAs act through a specific pathway, the so-called signal transduction p70(S6k) pathway in skeletal muscle (5). p70(S6k) is believed to control growth-related protein synthesis (5). There is also some evidence that branched chain amino acids are preferentially broken down for fuel during exercise, arguing for BCAA supplementation to offset this effect. If this is the case, this might be one mechanism where BCAA supplementation would hold off fatigue. Leucine seems particularly critical in stimulating overall protein synthesis. Leucine mediated signaling results in a stimulation of initiation of mRNA translation and involves increases in the phosphorylation status of the translational repression 4E-BP1 and the ribosomal protein S6 kinase S6K1mentioned above. It also requires sustained activation of the mammalian target of rapamycin (mTOR) protein kinase, a field of active research. Leucine, however, also signals to stimulate protein synthesis in skeletal muscle by a mammalian target of rapamycin protein kinase independent (i.e. rapamycin insensitive) pathway, suggesting that the amino acid may signal for protein synthesis through multiple pathways.
Interestingly, insulin is believed to exert at least part of its anabolic effect by activating the same p70(Sk6) pathway as leucine, but via different upstream channels. This argues for an additive role between elevated insulin levels and elevated BCAA levels in the promotion of anabolism.
There is another mechanism whereby BCAAs might prevent fatigue. We mentioned that BCAAs are used for fuel during exercise. As these amino acids become depleted, the ratio of tryptophan to BCAAs in the plasma rises (6). It turns out that tryptophan and BCAAs compete for the same amino acid transporter into the brain. The excess tryptophan in the brain is converted to serotonin, which induces a feeling of lethargy and fatigue. (Recall that tryptophan was widely used as a sleep aid.)
Interestingly men may have a greater need for BCAA supplementation than women. It is well established that women rely more on fat oxidation and less on glycogen and amino oxidation that do men during exercise. The BCAA leucine seems to be preferentially used among the amino acids as a fuel substrate in men (7).
TNF-Alpha and BCAA's
Tumor necrosis factor alpha (TNF-alpha) is a cytokine produced by immune cells in the body called monocytes and macrophages. TNF exerts a number of deleterious effects on the body, including muscle wasting, and locally produced igf-1 suppression, and general fatigue. While usually associated with illness, TNF-alpha levels are also high in hypogonadal patients and overtrained athletes. In one study, lipopolysachharide, a bacterial toxin that elevates TNF-alpha, was administered to rats. One group of rats was fed citrulline malate, and one group served as controls. The citrulline malate group performed much better on treadmill tests and exhibited less overall fatigue that did the controls (8).
These results may be of significance to overtrained athletes in whom TNF-alpha is elevated, and in anabolic steroid using athletes who are essentially hypogonadal post cycle. Citrulline malate may help alleviate the fatigue associated with both these conditions.
BCAAs may suppress TNF-alpha and its damaging effects on muscle tissue as well. In one study in animals, TNF-alpha was administered and diaphragm tissue was examined post mortem. Chronic TNF-alpha treatment produced a significant decline in the synthesis of all types of myofibrillar proteins, namely heavy chain myosin, light chain myosin and G-actin. TNF-alpha impaired peptide-chain initiation in diaphragm muscle was reversed by the branched-chain amino acids (BCAA) therapy of TNF-alpha treated rats. The authors concluded that
"These findings indicate a significant [inhibitory] role for TNF-alpha in the translational regulation of protein synthesis in skeletal muscle [which is reversed by BCAA administration ] (9) We see here a potential additive or even synergistic effect between citrulline malate and BCAAs in fighting muscle loss due to cytokines like TNF-alpha which are associated with illness, overtraining, and post anabolic steroid use.
In addition to blocking the muscle wasting catabolic effects of pro-inflammatory cytokines, BCAAs also seem to fight a tug of war with catabolic glucocorticoids. This suggests that under conditions such as stress or overtraining, BCAAs might help alleviate the catabolic effects of cortisol (10).