Citrulline is a non-essential amino acid that is one of the most important regulators of the urea cycle and of the ammonia detoxification — it is the key intermediate in the urea cycle, where it is synthesised from the ornithine by the ornithine transcarbamylase (OTC) enzyme and is then converted to the arginine by the argininosuccinate synthetase (ASS) enzyme, and it is the primary means by which the liver removes the ammonia (NH3) from the bloodstream and converts it to the urea for excretion in the urine. The citrulline is unique among the amino acids in that it is not incorporated into the proteins (it is a non-protein amino acid), and it functions almost exclusively as an intermediate in the urea cycle and as a precursor of the arginine and the nitric oxide (NO). The citrulline is synthesised primarily in the intestinal enterocytes (from the glutamine and the ornithine) and is released into the bloodstream for delivery to the liver and the kidneys, where it is converted to the arginine. The deficiency of the citrulline leads to the impaired urea cycle function, the elevated blood ammonia levels (hyperammonaemia), the fatigue, and the hepatic dysfunction that are the hallmark features of the citrulline deficiency and of the urea cycle disorders. The normal plasma citrulline level is approximately 20-50 µmol/L, and levels below this range indicate the citrulline deficiency that may require supplementation or dietary modification.
Citrulline and the Exercise Performance
Citrulline supports the exercise performance primarily through its role as a precursor of the arginine and the NO that regulate the blood flow and the oxygen delivery to the working muscles — the citrulline is converted to the arginine in the kidneys and the endothelial cells, and this conversion provides a more sustained and more efficient increase in the arginine levels than the direct arginine supplementation (because the citrulline bypasses the hepatic metabolism of the arginine that reduces the bioavailability of the orally administered arginine). The citrulline supplementation (at doses of 6-8g, taken 30-60 minutes before the exercise) has been shown to increase the plasma arginine levels by 50-70% and to increase the NO production by 30-50% — with concurrent improvements in the exercise performance, the reduction of the muscle soreness, and the faster recovery between the training sessions. The citrulline is particularly effective for the high-intensity exercise and for the endurance exercise, where the increased oxygen delivery to the working muscles and the reduced ammonia accumulation are the primary determinants of the performance.
The clinical importance of the citrulline for the exercise performance and for the recovery is underscored by the observation that the citrulline supplementation improves the exercise performance and reduces the muscle soreness in athletes and in the exercising adults. A study in 40 resistance-trained athletes found that the supplementation with the citrulline at 8g before the resistance training significantly improved the repetitions performed (by 10-15%), reduced the ratings of perceived exertion (RPE) (by 10-15%), and reduced the muscle soreness 24 and 48 hours after the training (by 20-25%) — demonstrating the potent and clinically meaningful ergogenic effect of the citrulline in resistance-trained athletes.
Practical Application
For general citrulline support for the exercise performance and for the ammonia detoxification, the evidence-based approach is to supplement with the L-citrulline at 4-8g daily (as the pure citrulline powder or capsules, taken in divided doses of 2-4g). The citrulline should be taken on an empty stomach (30-60 minutes before the exercise or the meals) for the best absorption and for the maximum NO production effect. The citrulline is generally well-tolerated with no significant adverse effects at the doses that are used for the exercise performance (up to 10g daily), though some people may experience mild gastrointestinal discomfort at the higher doses. For comprehensive citrulline support and exercise performance, citrulline pairs well with the arginine (which is converted from the citrulline and which works synergistically with the citrulline for the NO production and for the cardiovascular protection — the combination of the citrulline and the arginine is one of the most effective and most evidence-based combinations for the NO production and for the exercise performance, and it is significantly more effective than either compound alone for the increase of the arginine levels and for the NO production), with the leucine (which is the primary amino acid that stimulates the muscle protein synthesis and which works synergistically with the citrulline for the muscle gain and for the recovery — the combination of the citrulline and the leucine is one of the most effective combinations for the resistance training performance and for the muscle growth, and it is particularly useful for the bodybuilders and the strength athletes), and with the beta-alanine (which is a precursor of the carnosine and which works synergistically with the citrulline for the buffering of the muscle acidity during the high-intensity exercise — the combination of the citrulline and the beta-alanine is one of the most effective combinations for the high-intensity exercise performance and for the delay of the muscle fatigue during the sprinting and the high-intensity resistance training).
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