Citrulline Malate

By Jim Stoppani, PhD
Owner – JYM Supplement Science

malateEach dose of Pre JYM provides 6 grams of citrulline malate at a 2:1 ratio of citrulline to malate. No preworkout supplement on the market even comes close to providing this much citrulline malate or this much citrulline, period. And many of those preworkouts with underdosed citrulline malate use a 1:1 ratio of citrulline to malate. That means that you are getting even less of the critical amino acid citrulline than you realize.

Why did I include so much citrulline malate in Pre JYM? Because I know how effective this amino acid is for boosting performance in the gym. And 6 grams is the minimum dose that is shown to be effective in clinical studies. Anything less isn’t even worth taking.

Citrulline malate is the amino acid citrulline attached to a molecule of malic acid (malate), or in the case of the form I have used in Pre JYM,  two molecules of citrulline attached to one molecule of malate. Research confirms that supplementing with citrulline malate provides significant increases in exercise performance, when enough is taken. In the gym, my other lab, I’ve found that taking this much citrulline malate before workouts not only provides a significant strength and endurance boost during workouts, but it also provides an incredible pump. But even if you didn’t want to take my word for it, the research published on citrulline malate, and citrulline, supports this. And to further promote muscle pumps, this massive dose of citrulline malate gets a helping hand from other NO boosters that work by different methods, such as beet extract, N-acetyl L-cysteine (NAC), taurine, and even caffeine.

Citrulline is an amino acid closely related to the amino acid arginine. If you’ve done some reading on nitric oxide (NO) boosters, then you should know the arginine-nitric oxide pathway. This pathway is utilized by the body to convert arginine into nitric oxide (NO) with help from the enzyme nitric oxide synthase (NOS), which catalyzes the reaction. Increasing NO levels in blood vessels relaxes the blood vessels, allowing them to widen or dilate. Relaxing or dilating the blood vessels helps to deliver more blood flow to tissues like muscle fibers.

The two main benefits of greater blood flow to muscle fibers is better exercise energy/endurance and bigger muscles pumps during workouts. The greater endurance and energy is due to the fact that pushing more blood to working muscles delivers more oxygen and nutrients to them. It enhances muscle pump during workouts due to the fact that the blood is more than 50% water. When you train, your muscle cells create waste products that pull water into them. With greater blood flowing to the muscles there is more water that the muscle cells can pull into them, resulting in a bigger muscle pump. While some experts feel that the muscle pump has no true physiological significance, the truth is that it can lead to long-term muscle growth. This is due to the fact that the bigger muscle pump places a bigger stretch on the membranes of the muscle cells. This stretch signals chemical reactions that instigate long-term muscle growth by increasing muscle protein synthesis.

Some experts also argue that NO boosters offer no benefit to healthy individuals, especially during exercise. And it’s hard to argue with them if you look just at the research. Studies on NO-boosting ingredients, like arginine, show mixed results. However, in the gym with thousands of men and women, I have seen definite benefits that include greater strength and endurance, bigger muscle pumps and greater muscle growth. And one of the more recent studies on arginine reported that healthy subjects consuming arginine 30 minutes before a biceps workout increased biceps blood volume during the workout by over 100%.

Another question that you may ask is why would I use citrulline instead of arginine. As it turns out, citrulline appears to be an even better NO booster than arginine. This has been shown in a couple of studies. The first one found that subjects taking equivalent doses of citrulline and arginine had higher arginine blood levels when they took citrulline versus when they took arginine.  A later study from German researchers reported that it took just half the amount of citrulline as arginine to raise arginine blood concentrations to an equivalent level. The German researchers also found that a 3 grams dose of citrulline produced the highest increase in arginine and NO levels. The greater effectiveness of citrulline versus arginine itself appears to be due to excessive breakdown of arginine in the body after it is consumed. This is due to activity of the enzyme arginase in the intestines and liver. So a good portion of the arginine that is consumed is destroyed before it even leaves the intestines. The arginine that makes it through the intestines intact is directed straight to the liver, where it meets its fate with more arginase waiting for it. In fact, one study suggests that the amount of arginine consumed from oral supplements that was utilized in NO production was less than 1% of that consumed.

Using citrulline in place of arginine allows for higher arginine levels and higher NO production. This is because citrulline is not broken down in the intestines and bypasses the liver and goes straight to the blood vessels. There, citrulline is converted to arginine and then NO, which relaxes the smooth muscle cells of the blood vessels, causing dilation. One study found that over 80% of L-citrulline is converted to arginine in the blood vessels. While a study in professional cyclists showed that those supplementing with citrulline malate had a significant increase in NO production during exercise.

Supplementing with citrulline can also elevate growth hormone (GH) levels. This works through arginine’s ability to inhibit the hormone growth hormone inhibiting hormone (GHIH) or somatostatin, which normally inhibits GH production. By inhibiting this hormone that inhibits GH, arginine increases the production and release of GH from the anterior pituitary gland, which leads to higher blood levels of GH. Spanish researchers reported higher GH levels in athletes during exercise when taking citrulline beforehand. Having higher GH levels during workouts may promote greater gains in muscle size and strength. It can also encourage greater fat burning during workouts. This is due to an increase in lipolysis, which means that GH encourages a greater release of fat from fat cells so that it can be burned away for fuel during the workout.

Citrulline also has the ability to promote exercise endurance and blunt fatigue through its ability to enhance the removal of ammonia and lactic acid from the blood. High ammonia levels build up during intense exercise, due to the metabolism of the BCAAs by the muscle for fuel. The high ammonia level limits the ability of the muscles to contract with full force and impairs muscle endurance. Lactic acid dissociates into hydrogen ions and these also impair muscle contraction. By enhancing the clearance of ammonia and lactate, citrulline allows for faster recovery between sets and can allow for greater muscle endurance.

Taking citrulline in the form of citrulline malate also provides the additional benefit of malate, which is involved in the Krebs cycle to generate energy aerobically in the form of ATP (adenosine triphosphate). ATP is the energy currency of every cell. In muscle cell it is used to fuel muscle contraction, such as during exercise. Research in exercising humans shows that citrulline malate significantly improves the amount of ATP that the muscles are able to regenerate and enhances the rate that phosphocreatine (PCr) is regenerated. One study reported that subjects consuming 6 grams of citrulline malate for 15 days experienced an increase in ATP production during exercise by 35% and a 20% increase in phosphocreatine recovery after exercise. Phosphocreatine is what creatine is converted into inside the muscle cells through the addition of a high-energy phosphate group. Creatine donates this phosphate group during intense exercise, such as weight lifting, to produce ATP quickly to power muscle contractions that are required to lift the weight. This means that supplementing with citrulline malate can increase endurance to allow you to go longer, but also allow you to recover faster between sets, helping you to complete more reps per set later in your workouts.

The graph below shows the greater percent increase in ATP production and phosphocreatine recovery that subjects experienced after taking 6 grams of citrulline malate for 15 days as compared to before supplementation.

malate_graph_1

Another way that citrulline malate may enhance exercise endurance is by increasing the use of BCAAs as a fuel source by muscle fibers. A 2010 study published in the European Journal of Applied Physiology found that competitive cyclists taking 6 grams of citrulline malate before a bout of intense cycling had a higher flux of BCAAs into their muscle cells than those taking the placebo. Since the BCAAs are a potent energy source during exercise, this can allow for greater energy during workouts. This synergy between citrulline mallate and the BCAAs is one of many reasons why I chose to include these supplements together in Pre JYM. In this formula, the citrulline malate can work to help drive more of the BCAAs into the working muscle fibers, which can enhance energy during the workout and then promote better muscle growth after the workout is over. The researchers in the study discussed above, also suggested that the higher flux of BCAAs could also better prepare the muscle for recovery and growth after the workout is over.

A 2010 study in the Journal of Strength and Conditioning Research showed just how effective taking citrulline malate before strength training can be. They had weight-trained subjects supplement with citrulline malate or a placebo one hour before a chest workout that consisted of 16 sets and included exercises such as bench presses, incline bench presses and flyes. They found that from set 3 on the subjects were able to complete at least one more rep, and in some cases two more reps, when supplementing with citrulline malate as compared to the placebo. Being able to complete one or two more reps on most sets of a workout can make a big difference in the results you get in both muscle size and strength over time.

The graph below shows the greater number of reps subjects were able to complete during a high volume chest workout when taking citrulline malate versus a placebo.

malate_graph_2

 

References:

Haussinger, D., et al. Regulation of cell function by the cellular hydration state. Am J Physiol 267(3 Pt 1):E343-E355, 1994.

Haussinger, D. Control of protein turnover by the cellular hydratation state. Ital J Gastroenterol 25, 42–48, 1993.

Alvares, T. S., et al. Acute l-arginine supplementation increases muscle blood volume but not strength performance. Appl Physiol Nutr Metab. 2012 Feb;37(1):115-26.

Kuhn, K. P., et al. Oral citrulline effectively elevates plasma arginine levels for 24 hours in normal volunteers. Circulation 2002; 106: II1–766S.

Schwedhelm, E., et al. “Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism,” British Journal of Clinical Pharmacology, 65(1):51-9, 2008.

Morris, S. M., Jr. Enzymes of arginine metabolism. J Nutr 2004; 134: 2743S–7S.

Castillo, L., et al. Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man. Proc Natl Acad Sci USA 1993; 90: 193–7.

Böger, R. H., et al, Hypercholesterolemia impairs basal nitric oxide synthase turnover rate: a study investigating the conversion of L-[guanidino-15N2]-arginine to 15N-labeled nitrate by gas chromatography-mass spectrometry. Nitric Oxide 2004; 11: 1–8.

Solomonson, L. P., et al. The caveolar nitric oxide synthase/arginine regeneration system for NO production in endothelial cells. J Exp Biol 206:2083–2087, 2003.

Sureda, A., et al. Effects of L-citrulline oral supplementation on polymorphonuclear neutrophils oxidative burst and nitric oxide production after exercise. Free Radic Res. 2009 Sep;43(9):828-35.

Sureda, A., et al. L-citrulline-malate influence over branched chain amino acid utilization during exercise. Eur J Appl Physiol. 2010 Sep;110(2):341-51.

Sanchez-Gonzalez MA., et al. The effects of short term L-citrulline supplementation on wave reflection responses to cold exposure with concurrent isometric exercise. Am J Hypertens. 2013 Apr;26(4):518-26.

El-Bassossy HM, Arginase inhibition alleviates hypertension in the metabolic syndrome. Br J Pharmacol, in press, 2013.

Wagenmakers, A. J., et al. Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle’s disease. Int J Sports Med. 1990 May;11 Suppl 2:S101-13.

Takeda, K., et al. Effects of citrulline supplementation on fatigue and exercise performance in mice. J Nutr Sci Vitaminol (Tokyo). 2011;57(3):246-50.

Goubel, F., et al. Citrulline malate limits increase in muscle fatigue induced by bacterial endotoxins. Can J Physiol Pharmacol. 1997 Mar;75(3):205-7.

Callis, A., et al. 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.

Bendahan, D., et al. Citrulline/malate promotes aerobic energy production in human exercising muscle. Br J Sports Med. 2002 Aug;36(4):282-9.

Giannesini, B., et al. Citrulline malate supplementation increases muscle efficiency in rat skeletal muscle. Eur J Pharmacol. 2011 Sep 30;667(1-3):100-4.

Pérez-Guisado, J. and Jakeman, P. M. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness.