Effects of leucine and its metabolite β‐hydroxy‐β‐methylbutyrate on human skeletal muscle protein metabolism
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Key points: The branched‐chain amino acid (BCAA) leucine acts as both a ‘trigger’ for the initiation of protein synthesis, and as a substrate for newly synthesized protein. As a BCAA, leucine can be metabolized within skeletal muscle, leaving open the possibility that leucine metabolites might possess anabolic properties. One metabolite in particular, β‐hydroxy‐β‐methylbutyrate (HMB), has shown positive effects on lean body mass and strength following exercise, and in disease‐related muscle wasting, yet its impact on acute human muscle protein turnover is undefined. We report here that HMB stimulates muscle protein synthesis to a similar extent to leucine. HMB was also found to decrease muscle protein breakdown. Our observation that HMB enhances muscle protein anabolism may partly (or wholly) underlie its pre‐defined anabolic/anti‐catabolic supplemental efficacy in humans. Abstract Maintenance of skeletal muscle mass is contingent upon the dynamic equilibrium (fasted losses–fed gains) in protein turnover. Of all nutrients, the single amino acid leucine (Leu) possesses the most marked anabolic characteristics in acting as a trigger element for the initiation of protein synthesis. While the mechanisms by which Leu is ‘sensed’ have been the subject of great scrutiny, as a branched‐chain amino acid, Leu can be catabolized within muscle, thus posing the possibility that metabolites of Leu could be involved in mediating the anabolic effect(s) of Leu. Our objective was to measure muscle protein anabolism in response to Leu and its metabolite HMB. Using [1,2‐ 13 C 2 ]Leu and [ 2 H 5 ]phenylalanine tracers, and GC‐MS/GC‐C‐IRMS we studied the effect of HMB or Leu alone on MPS (by tracer incorporation into myofibrils), and for HMB we also measured muscle proteolysis (by arteriovenous (A–V) dilution). Orally consumed 3.42 g free‐acid (FA‐HMB) HMB (providing 2.42 g of pure HMB) exhibited rapid bioavailability in plasma and muscle and, similarly to 3.42 g Leu, stimulated muscle protein synthesis (MPS; HMB +70% vs . Leu +110%). While HMB and Leu both increased anabolic signalling (mechanistic target of rapamycin; mTOR), this was more pronounced with Leu (i.e. p70S6K1 signalling ≤90 min vs . ≤30 min for HMB). HMB consumption also attenuated muscle protein breakdown (MPB; −57%) in an insulin‐independent manner. We conclude that exogenous HMB induces acute muscle anabolism (increased MPS and reduced MPB) albeit perhaps via distinct, and/or additional mechanism(s) to Leu.
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Leucine alone appears to be the metabolic trigger for muscle protein synthesis.
“However, perhaps the most important candidate is the key essential amino acid leucine, as it alone appears to be the metabolic trigger for muscle protein synthesis [87, 88].”
From Periodized Nutrition for Athletes (2017) · cites this paper as [88]
The leucine metabolite HMB may also trigger protein feeding-induced increases in MPS.
“The key trigger for the protein feeding induced increases in MPS seems to be the leucine content of the digested protein [107] and possibly the leucine metabolite HMB (β-Hydroxy β-methylbutyrate) [108].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [108]
Both leucine and HMB activate mTORC1 in human skeletal muscle when consumed.
“Both of which activate mTORC1 in human skeletal muscle when consumed [108].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [108]
HMB consumption attenuated muscle protein breakdown (MPB; -57%) in an insulin-independent manner.
“HMB consumption also attenuated muscle protein breakdown (MPB; -57%) in an insulin-independent manner [108].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [108]
HMB supplementation resulted in larger gains in muscle function associated with resistance training.
“and resulted in larger gains in muscle function associated with resistance training [180] on [108].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [108]
Oral consumption of HMB (3.42 g free-acid providing 2.42 g pure HMB) exhibited rapid bioavailability in plasma and muscle.
“oral consumption of HMB (3.42 g free-acid (FA-HMB) providing 2.42 g of pure HMB) exhibited rapid bioavailability in plasma and muscle”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [108]
Oral consumption of HMB (3.42 g free-acid providing 2.42 g pure HMB) stimulated muscle protein synthesis (MPS; HMB +70% vs. Leu +110%).
“similarly to 3.42 g Leucine (Leu), stimulated muscle protein synthesis (MPS; HMB +70% vs. Leu +110%).”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [108]
mTORC1 activation was more pronounced in the Leu group compared to HMB.
“however mTORC1 activation was more pronounced in the Leu group compared to HMB [108]”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [108]
The mechanism of Leu action may function in additional processes compared to HMB.
“suggesting that the mechanism of Leu action may function in additional processes compared to HMB (Figure 2).”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [108]
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- Authors
- Wilkinson, D. J., Hossain, T., Hill, D. S., Phillips, B. E., Crossland, H., Williams, J., Loughna, P., Churchward‐Venne, T. A., Breen, L., Phillips, S. M., Etheridge, T., Rathmacher, J. A., Smith, K., Szewczyk, N. J., & Atherton, P. J.
- Affiliations
- University of Nottingham (GB)
- McMaster University (CA)
- Bournemouth University (GB)
- Iowa State University (US)
- Corresponding author
- Wilkinson, D. J.
- Atherton, P. J.
- ORCID
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2013-04-26
- Volume
- 591
- Issue
- 11
- Pages
- 2911-2923
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC3690694
- OpenAlex
- W2167013734
- Cited by
- 484
- References
- 38
- Citations by year
- 2026: 33 · 2025: 35 · 2024: 33 · 2023: 35 · 2022: 43 · 2021: 46 · 2020: 58 · 2019: 27 · 2018: 39 · 2017: 31 · 2016: 35 · 2015: 34 · 2014: 25 · 2013: 10
- FWCI
- 20.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Nottingham ePrints (University of Nottingham) (submittedVersion, cc-by)
- Figshare (submittedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, other-oa)
- Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
- Funders
- Metabolic Technologies
- Research Councils UK
- National Institutes of Health
- Natural Sciences and Engineering Research Council of Canada
- Medical Research Council (MR/K00414X/1, G0801271)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR054342)
- 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 › Medicine › Physiology › Nutrition and Health in Aging
- Keywords
- leucine, beta-hydroxy-beta-methylbutyrate, skeletal muscle protein synthesis, muscle protein degradation, muscle protein turnover, branched-chain amino acids, leucine metabolism, mTOR signaling, muscle anabolism, muscle atrophy, dietary supplementation, isotope tracers, lean body mass, resistance training, sarcopenia
- MeSH terms
- Administration, Oral, Humans, Leucine, Male, Tissue Distribution, Protein Biosynthesis, Valerates, Muscle, Skeletal, Young Adult, Proteolysis
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