Citrulline malate

Citrulline Malate is a combination of the amino acid citrulline with malate. This supplement has a somewhat complex mechanism of action. Within many of your endothelial cells, including those of the vascular system, is a molecule called guanosine Triphosphate. This is 1 guanosine with 3 phosphates, and it can behave in a similar manner as ATP – with hydrolysis removing one of its phosphate bonds to release energy.

A key role of GTP, however, is to be converted into cyclic Guanosine Monophosphate (cGMP) which is simply a guanosine with one phosphate group that has become cyclical (linked into a circle). This occurs due to the action of an enzyme called Guanolate Cyclase as you see below:

cGMP is the first step in a cascade resulting in vasodilation, a widening of blood vessels.

Guanolate cyclase is not active under normal circumstances, however. It’s activated by Nitric Oxide (NO) – a small soluble molecule able to diffuse across the cell walls on the interior wall of blood vessels and enter the cytoplasm. Nitric oxide is produced via the action of nitric oxide synthase (NOS) using the amino acid arginine. This means that serum levels of arginine are rate limiting for nitric oxide production, and so an increase in arginine concentration in the blood leads to an increase of nitric oxide, then guanolate cyclase, and in turn GMP.

GMP is then used to stimulate another enzyme called protein kinase G (PKG). Kinases add phosphate groups to proteins, and so PKG is then free to alter and ‘activate’ a number of other intracellular proteins, resulting in vasodilation.

That vasodilation leads to improved blood flow, meaning a greater delivery of nutrients and oxygen to muscle tissue, and an increased rate of removal for some of the waste products that result in fatigue such as ammonia. Increased vasodilation can therefore improve endurance alongside muscle pumps (which may be beneficial to hypertrophy to a small degree, owing to cellular swelling).

Where citrulline malate comes into this, is in the fact that citrulline supplementation increases plasma arginine levels very effectively (citrulline is converted to arginine via the kidneys once in the blood) but oral supplementation of arginine does not, meaning it does not increase plasma NO.

To recap – supplementary citrulline malate leads to increased plasma arginine, which results in increased nitric oxide via the enzyme nitric oxide synthase, which crosses the cell membranes of cells in blood vessels and activates guanolate cyclase, thus converting GTP to cGMP and activating a cascade of reactions that result in vasodilation.

To add to that, the malate from citrulline malate, when separated from citrulline, can influence the amount of ATP that can be produced during exercise, by 34% in a study by Bendahan in 2002.

When translated to human trials, chronic citrulline malate supplementation appears to reduce perceived fatigue, increase time to exhaustion, increase potential training volume completed, reduce muscle soreness and improve performance of exercise completed on consecutive days. Of note is that many medications for angina or similar conditions use this pathway to help ease blood flow, and so an NO based supplement may be beneficial for those with poor blood flow, and it can be effective at relieving some amount of physiologically grounded erectile dysfunction. Despite being shown to improve work capacity, there is no evidence as yet to suggest that Citrulline Malate can improve power output.

To take for erectile dysfunction, take 1000mg 3 times per day with meals. For sporting performance a dose of 6000-8000mg must be taken shortly prior to a workout.