Leucine Activates system A Amino Acid Transport in Skeletal Muscle Cells
Just as glucose uptake into cells is dependent upon a family of so called GLUT (Glucose Transporters), amino acids are transported into cells by a distinct family of transporters. One main transport system is the so-called System A. In vitro studies have shown that leucine upregulates System A transporters, allowing for greater entry of a number of amino acids into muscle cells (11). It should be noted that one of the anabolic effects of IGF-1 is believed to be upregulation of this same transport system. So in this sense leucine may share at least one of the anabolic effects associated with insulin like growth factor.

So we have seen that amino acids, and leucine in particular are capable of activating signal transduction pathways in an almost hormone like manner. They are much more than simple nutrients in this regard. To quote from one recent review,

"The protein kinase mTOR is a common intermediate in both nutrient and hormone signal transduction pathways. Signaling through mTOR is enhanced by nutrients and anabolic hormones, such as insulin or IGF-I and repressed by elevation of cAMP or activation of AMPK suggesting that one function of mTOR is to integrate the anabolic response to nutrients and insulin and the catabolic response to counter-regulatory hormones, such as glucagon...Although other amino acids have been shown to increase signaling through mTOR, leucine is arguably the most potent of the amino acids in activating the pathway." (12)

The importance of leucine to post resistance exercise recovery is highlighted in another recently published study where participants undertook a bout of resistance exercise and were fed either carbohydrates alone, carbohydrates plus whey protein, or a combination of carbs, whey and leucine (13). Subjects received a beverage volume of 3 ml.kg-1 every 30 minutes to ensure a given dose of 0.3 g carbohydrate.kg-1 (50% as glucose and 50% as maltodextrin) and 0.2 g.kg-1 of a protein hydrolysate [whey] every h, with or without the addition of 0.1 g.kg-1.h-1 leucine. To quote from the report,

"Mixed muscle [protein synthesis rate], measured over a 6h period of post-exercise recovery, was significantly greater in the CHO+PRO+leu trial compared to the CHO, with intermediate values observed in the CHO+PRO trial . We conclude that the co-ingestion of protein and leucine stimulates muscle protein synthesis and optimizes whole-body protein balance when compared to the intake of carbohydrate only."

Glutamine

Before leaving the subject of BCAAs and citrulline, it might be worthwhile to briefly discuss the role of another amino acid, glutamine that is both quite popular and controversial as a supplement. The bulk of the research suggests that under normal circumstances the body is capable of making adequate amounts of glutamine from the branched chain amino acids discussed above. However, when the body is taxed by illness, sepsis, cancer, cachexia, and trauma, and perhaps chronic overtraining, the body may become depleted in BCAAs. The BCAAs released to circulation may be used for protein synthesis or synthesis of alanine and glutamine. Glutamine and/or alanine infusion has an inhibitory effect on the breakdown of body proteins and decreases BCAA catabolism in postabsorptive control, endotoxemic, and irradiated rats. This helps preserve muscle mass under these conditions (14). So while glutamine supplementation might not be absolutely necessary with an adequate intake of amino acids, especially BCAAS, it’s hard to see how glutamine supplementation could hurt, and might actually be beneficial.

So in summary we can obtain an additive anti-fatigue effect by combining citrulline malate with branched-chain amino acids. The former replenishes TCA intermediates allowing for enhanced ATP production, while the latter preserves vital muscle tissue BCAAs and blocks the entry of fatigue inducing tryptophan into the brain. Additional glutamine supplementation might be beneficial should the body become depleted in BCAAs during strenuous prolonged exercise or illness.

Dosage of Citrulline Malate

Concerning dosage of citrulline malate in humans, based on the work in (2), 6 grams per day of citrulline malate taken in two divided doses during the day may be the optimal dose. None of the studies in humans suggested any serious side effects, and the drug appears to be well tolerated.

References

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Bendahan D, Mattei JP, Ghattas B, Confort-Gouny S, Le Guern ME, Cozzone PJ. Citrulline/malate promotes aerobic energy production in human exercising muscle. Br J Sports Med 2002 Aug;36(4):282-9

Callis A, Magnan de Bornier B, Serrano JJ, Bellet H, Saumade R. Activity of citrulline malate on acid-base balance and blood ammonia and amino acid levels. Study in the animal and in man. Arzneimittelforschung 1991 Jun;41(6):660-3.

Blomstrand E, Saltin B. BCAA intake affects protein metabolism in muscle after but not during exercise in humans. Am J Physiol Endocrinol Metab 2001 Aug;281(2):E365-74

Karlsson HK, Nilsson PA, Nilsson J, Chibalin AV, Zierath JR, Blomstrand E. Branched-chain amino acids increase p70S6k phosphorylation in human skeletal muscle after resistance exercise. Am J Physiol Endocrinol Metab. 2004 Jul;287(1):E1-7

Blomstrand E, Celsing F, Newsholme EA. Changes in plasma concentrations of aromatic and branched-chain amino acids during sustained exercise in man and their possible role in fatigue. Acta Physiol Scand 1988 May;133(1):115-21

Lamont LS, McCullough AJ, Kalhan SC. Gender differences in the regulation of amino acid metabolism. J Appl Physiol. 2003 Sep;95(3):1259-65

Verleye M, Heulard I, Stephens JR, Levy RH, Gillardin JM. Effects of citrulline malate on bacterial lipopolysaccharide induced endotoxemia in rats. Arzneimittelforschung 1995 Jun;45(6):712-5

Cheema IR, Hermann C, Postell S, Barnes P. Effect of chronic excess of tumour necrosis factor-alpha on contractile proteins in rat skeletal muscle. Cytobios. 2000;103(404):169-76.

Liu Z, Jahn LA, Long W, Fryburg DA, Wei L, Barrett EJ. Branched chain amino acids activate messenger ribonucleic acid translation regulatory proteins in human skeletal muscle, and glucocorticoids blunt this action. J Clin Endocrinol Metab 2001 May;86(5):2136-43.

McDowell HE, Christie GR, Stenhouse G, Hundal HS. Leucine activates system A amino acid transport in L6 rat skeletal muscle cells. Am J Physiol. 1995 Nov;269(5 Pt 1):C1287-94.

Kimball SR, Jefferson LS. Amino acids as regulators of gene expression. Nutr Metab (Lond). 2004 Aug 17;1(1):3

Koopman R, Wagenmakers AJ, Manders RJ, Zorenc AH, Senden JM, Gorselink M, Keizer HA, van Loon LJ. The combined ingestion of protein and free leucine with carbohydrate increases post-exercise muscle protein synthesis in vivo in male subjects. Am J Physiol Endocrinol Metab. 2004 Nov 23

Holecek M. Relation between glutamine, branched-chain amino acids, and protein metabolism. Nutrition. 2002 Feb;18(2):130-3

Nakata M, Yada T. Endocrinology: nitric oxide-mediated insulin secretion in response to citrulline in islet beta-cells. Pancreas. 2003 Oct;27(3):209-13

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