Build muscles but eat little protein? Use L-citrulline


Athletes who for whatever reason don’t eat much protein might benefit from L-citrulline [structural formula below]. We draw this tentative conclusion from a human study that researchers at the Mayo Clinic in the US published in Clinical Nutrition. If the results are to be believed, L-citrulline has anabolic qualities in combination with a low-protein diet.

Animal studies have shown that L-citrulline supplementation protects against muscle mass breakdown while on a low-calorie diet. This is why the researchers wondered whether L-citrulline would have the same effect when combined with a low-protein diet.

So they did a small experiment with 8 subjects, who ate a low-protein diet for three days. They were given just under 0.7 g protein per kg bodyweight daily.

On the fourth day the subjects were given extra L-citrulline in soluble form on an empty stomach. Over a period of 8 hours they drank 11-24 g L-citrulline in total. The dose of L-citrulline depended on their lean body mass: the higher this was, the more L-citrulline they were given.

On another occasion the subjects were given a similar quantity of amino acids, which – like L-citrulline – were not essential.

Muscle protein
The figure below shows that L-citrulline boosted the synthesis of new muscle protein [FSR]. In non-muscle tissue L-citrulline had no effect on protein synthesis.


The researchers measured the activity of a number of genes in the muscle cells, but were unable to work out exactly how L-citrulline works. They didn’t detect any effect on hormones such as insulin and IGF-1 either.

“The current pilot study, the first performed in humans, demonstrates that oral ingestion of citrulline stimulated muscle protein synthesis in healthy participants while on a short-term low-protein diet”, the researchers write. “This anabolic action of citrulline is independent of insulin action and is specific of muscle. Overall, this novel finding opens the potential opportunity for clinical application of citrulline in situations where muscle anabolism is diminished.”

Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet – A pilot study.


Amino acid (AA) availability is critical to maintain protein homeostasis and reduced protein intake causes a decline in protein synthesis. Citrulline, an amino acid metabolite, has been reported to stimulate muscle protein synthesis in malnourished rats.

To determine whether citrulline stimulates muscle protein synthesis in healthy adults while on a low-protein diet, we studied 8 healthy participants twice in a cross-over study design. Following a 3-days of low-protein intake, either citrulline or a non-essential AA mixture (NEAA) was given orally as small boluses over the course of 8 h. [ring-(13)C6] phenylalanine and [(15)N] tyrosine were administered as tracers to assess protein metabolism. Fractional synthesis rates (FSR) of muscle proteins were measured using phenylalanine enrichment in muscle tissue fluid as the precursor pool.

FSR of mixed muscle protein was higher during the administration of citrulline than during NEAA (NEAA: 0.049 ± 0.005; citrulline: 0.060 ± 0.006; P = 0.03), while muscle mitochondrial protein FSR and whole-body protein turnover were not different between the studies. Citrulline administration increased arginine and ornithine plasma concentrations without any effect on glucose, insulin, C-peptide, and IGF-1 levels. Citrulline administration did not promote mitochondria protein synthesis, transcripts, or citrate synthesis.

Citrulline ingestion enhances mixed muscle protein synthesis in healthy participants on 3-day low-protein intake. This anabolic action of citrulline appears to be independent of insulin action and may offer potential clinical application in conditions involving low amino acid intake.

Copyright © 2014. Published by Elsevier Ltd.

PMID: 24972455 PMCID: PMC4309748 DOI: 10.1016/j.clnu.2014.04.019

[PubMed – indexed for MEDLINE] Free PMC Article