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

Clin Nutr. 2015 Jun;34(3):449-56. doi: 10.1016/j.clnu.2014.04.019. Epub 2014 May 4.


Background & aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Citrulline; Muscle; Phenylalanine; Protein synthesis.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arginine / blood
  • Blood Glucose / metabolism
  • C-Peptide / blood
  • Citrulline / administration & dosage*
  • Cross-Over Studies
  • Diet, Protein-Restricted*
  • Dietary Proteins / administration & dosage
  • Female
  • Humans
  • Insulin / blood
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Mitochondrial Proteins / biosynthesis*
  • Muscle Proteins / biosynthesis*
  • Ornithine / blood
  • Phenylalanine / administration & dosage
  • Pilot Projects
  • Protein Biosynthesis / drug effects
  • Tyrosine / administration & dosage
  • Young Adult


  • Blood Glucose
  • C-Peptide
  • Dietary Proteins
  • Insulin
  • Mitochondrial Proteins
  • Muscle Proteins
  • Citrulline
  • Tyrosine
  • Phenylalanine
  • Insulin-Like Growth Factor I
  • Arginine
  • Ornithine