Nutrient-Nutrient Interactions
Branched Chain Amino Acids (special reference to Leucine)
Branched-chain amino acids (BCAAs) are a group of three amino acids (leucine, isoleucine, and valine) that are involved in skeletal muscle synthesis and degradation. Of these three, leucine is commonly said to be the most “important” because it is the prime mediator of muscle protein synthesis (and appears to be the most common reason for supplementation with BCAAs).
When looking at citrulline ingestion at rest, a dose of 0.18 g/kg was found to improve nitrogen balance in one study when ingested in the fed state[1] whereas another study noted a failure with the same dose; both whole-body protein synthesis and leucine oxidation rates were unaffected.[2]
During exercise, 6 grams of citrulline taken by trained cyclists prior to a 137 km cycling test produced a reduction in plasma BCAAs relative to the control, and this effect was attributed to increased utilization of BCAAs for fuel.[3]
Citrulline does appear to interact with BCAA metabolism in the body, although human studies have produced differing results based on the context of the study.
Similar to how citrulline is able to restore muscle protein synthesis rates[4]PMD:16608884 and muscular function[5] during aging and malnourishment in rats via mTORc1-dependent means,[6][7] citrulline itself is a weak agonist (enough that it could be false positive from sensitizing mTORc1[4]). Conversely, leucine itself is a potent activator of mTORc1 activity.
Citrulline may positively mediate leucine's signaling through mTOR, which theoretically suggests that they are synergistic. The application of this combination in weight lifters has not yet been investigated, so the synergism is currently just a hypothesis rather than a demonstrated fact.
Glutathione
Citrulline increases levels of nitric oxide (NO), a vasodilator. Although NO effects are potent, the extent of vasodilation is limited by the short half life of NO, which is broken down by oxidation soon after it is formed.[8] One study found that taking reduced glutathione (GSH; a reducing agent) alongside citrulline may help to protect against the rapid oxidative destruction of NO. In vitro studies in human umbilical vein endothelial cells demonstrated that citrulline (0.3 mM) in combination with GSH (1 mM) resulted in significantly greater nitrite levels than vehicle-treated controls or citrulline alone. Similarly, 3-day treatment of rats with citrulline (500 mg/kg/day) and GSH (50 mg/kg/day) by oral gavage increased plasma nitric oxide levels more than a control or citrulline alone. The investigators also conducted a small human trial in which resistance-trained men were randomly assigned to orally ingest either a placebo or L-citrulline (2 g/day), GSH (1 g/day), or citrulline (2 g/day) in combination with GSH (200 mg/day) for 7 days, followed by a resistance exercise session. Consistent with in vitro and rat studies, participants who took GSH along with citrulline had significantly higher nitrite and nitric oxide levels at 30 minutes after exercise relative to placebo or citrulline alone.[8]
Supplementing with reduced glutathione (GSH) alongside citrulline may extend the half life of nitric oxide, potentially resulting in greater vasodilation compared to L-citrulline alone.
Nitrate
Nitrate is a small nitric oxide donor that is the main bioactive of beetroot juice.
Serum nitrite (reduced form of nitrate) appears to be increased during exercise after consumption of 6 grams of citrulline malate, which is thought to be an indicator of increased nitric oxide production.[9]
Sodium Bicarbonate
Sodium bicarbonate (baking soda) is an ergogenic supplement that is reported to increase physical performance, and although it is somewhat unreliable overall in doing so, it appears to be effective for short-duration activities characterized by metabolic acidosis ('the burn').
Citrulline administration appears to promote ureogenesis (production of urea) and secondarily promote the renal resorption of bicarbonate;[10] it is thought that citrulline may promote a slight buffering effect by preserving bicarbonate.[11]
A study assessing the synergism between citrulline and bicarbonate supplementation is currently not available.
Theoretically synergistic, but has not been directly investigated at this moment in time
Statins
One study in endothelial cells (in vitro) noted that the tested statin (simvastatin) was able to increase mRNA concentrations of eNOS (the enzyme in endothelial cells that produces nitric oxide from arginine) and thus was said to act synergistically with arginine and/or citrulline to improve blood pressure in participants with high cholesterol.[12]
Because simvastatin,[12] atorvastatin,[13][14] and lovastatin[15] (bioactive in red yeast rice) have all been noted to increase eNOS,[13] iNOS,[13][15] and nNOS[14] it is thought that this is a mechanism common to statin drugs in general.
Statin drugs may be able to increase expression of the enzyme that mediates the conversion of arginine into nitric oxide, and there is possible synergism for other processes pertaining to nitric oxide. This hypothesis has not yet been tested in a living system.
References
- ^Rougé C, Des Robert C, Robins A, Le Bacquer O, Volteau C, De La Cochetière MF, Darmaun DManipulation of citrulline availability in humansAm J Physiol Gastrointest Liver Physiol.(2007 Nov)
- ^Thibault R, Flet L, Vavasseur F, Lemerle M, Ferchaud-Roucher V, Picot D, Darmaun DOral citrulline does not affect whole body protein metabolism in healthy human volunteers: results of a prospective, randomized, double-blind, cross-over studyClin Nutr.(2011 Dec)
- ^Sureda A, Córdova A, Ferrer MD, Pérez G, Tur JA, Pons AL-citrulline-malate influence over branched chain amino acid utilization during exerciseEur J Appl Physiol.(2010 Sep)
- ^Le Plénier S, Walrand S, Noirt R, Cynober L, Moinard CEffects of leucine and citrulline versus non-essential amino acids on muscle protein synthesis in fasted rat: a common activation pathway?Amino Acids.(2012-Sep)
- ^Faure C, Raynaud-Simon A, Ferry A, Daugé V, Cynober L, Aussel C, Moinard CLeucine and citrulline modulate muscle function in malnourished aged rats.Amino Acids.(2012-Apr)
- ^Direct action of citrulline on muscle protein synthesis: role of the mTORC1 pathway
- ^Cynober L, de Bandt JP, Moinard CLeucine and citrulline: two major regulators of protein turnoverWorld Rev Nutr Diet.(2013)
- ^McKinley-Barnard S, Andre T, Morita M, Willoughby DSCombined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesisJ Int Soc Sports Nutr.(2015 Jun 10)
- ^Sureda A, Córdova A, Ferrer MD, Pérez G, Tur JA, Pons AL-citrulline-malate influence over branched chain amino acid utilization during exerciseEur J Appl Physiol.(2010 Sep)
- ^Callis A, Magnan de Bornier B, Serrano JJ, Bellet H, Saumade RActivity of citrulline malate on acid-base balance and blood ammonia and amino acid levels. Study in the animal and in manArzneimittelforschung.(1991 Jun)
- ^A Callis, B Magnan de Bornier, J J Serrano, H Bellet, R SaumadeActivity of citrulline malate on acid-base balance and blood ammonia and amino acid levels. Study in the animal and in manArzneimittelforschung.(1991 Jun)
- ^Berthe MC, Bernard M, Rasmusen C, Darquy S, Cynober L, Couderc RArginine or citrulline associated with a statin stimulates nitric oxide production in bovine aortic endothelial cells.Eur J Pharmacol.(2011-Nov-30)
- ^Ye Y, Martinez JD, Perez-Polo RJ, Lin Y, Uretsky BF, Birnbaum YThe role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin.Am J Physiol Heart Circ Physiol.(2008-Jul)
- ^Sei Nakata, Masato Tsutsui, Hiroaki Shimokawa, Takahiro Yamashita, Akihide Tanimoto, Hiromi Tasaki, Kiyoshi Ozumi, Ken Sabanai, Tsuyoshi Morishita, Osamu Suda, Hideyasu Hirano, Yasuyuki Sasaguri, Yasuhide Nakashima, Nobuyuki YanagiharaStatin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathwayArterioscler Thromb Vasc Biol.(2007 Jan)
- ^A Y Kolyada, A Fedtsov, N E Madias3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors upregulate inducible NO synthase expression and activity in vascular smooth muscle cellsHypertension.(2001 Nov)