Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet: A pilot study
Open accessAbstract
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.
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Creatine, citrulline, and leucine-rich feedings are best interpreted as compounds that help maintain a permissive metabolic and signalling environment in which mechanical loading can drive nucleolar expansion.
“Creatine [166,167], citrulline [168,169], and leucine-rich feedings [111,162] are best interpreted as compounds that help maintain a permissive metabolic and signalling environment in which mechanical loading can drive nucleolar expansion.”
From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [168]
The Introduction and Discussion (page unavailable) link citrulline to muscle protein synthesis after low protein intake and suggest mTOR signalling as a possible mechanism. They do not establish that citrulline maintains a permissive environment for mechanical loading or nucleolar expansion. (LLM, conf=0.85)
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“Citrulline has attracted interest because human studies suggest it can stimulate MPS in specific nutritional contexts, raising the possibility that it may influence how energy and substrates are partitioned toward protein synthesis [168,169].”
- Authors
- Jourdan, M., Nair, K. S., Carter, R. E., Schimke, J., Ford, G. C., Marc, J., Aussel, C., & Cynober, L.
- Affiliations
- Mayo Clinic (US)
- Université Paris Descartes (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hôpital Cochin (FR)
- Corresponding author
- Nair, K. Sreekumaran
- Venue
- Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 34
- Issue
- 3
- Pages
- 449-456
- ISSN
- 0261-5614 (ISSN-L)
- PMC
- PMC4309748
- OpenAlex
- W1963705531
- Cited by
- 73
- References
- 30
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 9 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 5
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Clinical Nutrition (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Institute for Functional Nanomaterials
- Société Française de Nutrition Entérale et Parentérale
- National Institutes of Health (R01 DK41973, UL1 TR000135)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Clinical Nutrition and Gastroenterology
- Keywords
- citrulline, muscle protein synthesis, low-protein diet, postabsorptive state, amino acid availability, fractional synthesis rate, phenylalanine tracer, L-arginine, ornithine, mitochondrial translation, whole-body protein turnover, healthy adults
- MeSH terms
- Adult, Arginine, Blood Glucose, C-Peptide, Citrulline, Dietary Proteins, Female, Humans, Insulin, Insulin-Like Growth Factor I, Male, Muscle Proteins, Ornithine, Phenylalanine, Pilot Projects, Protein Biosynthesis, Tyrosine, Cross-Over Studies, Diet, Protein-Restricted, Mitochondrial Proteins, Young Adult
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