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Effects of leucine and its metabolite ?-hydroxy-?-methylbutyrate on human skeletal muscle protein metabolism

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.

Effects of leucine and its metabolite ?-hydroxy-?-methylbutyrate on human skeletal muscle protein metabolism Thumbnail


D.J. Wilkinson

T. Hossain

D.S. Hill

Professor of Translational Physiology

H. Crossland

J. Williams

P. Loughna

T.A. Churchward-Venne

L. Breen

S.M. Phillips

T. Etheridge

J.A. Rathmacher

K. Smith

N.J. Szewczyk

P.J. Atherton


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 [1,2-13C2]Leu and [2H5]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.


Wilkinson, D., Hossain, T., Hill, D., Phillips, B., Crossland, H., Williams, J., …Atherton, P. (2013). Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism. Journal of Physiology, 591(11),

Journal Article Type Article
Publication Date Jun 1, 2013
Deposit Date Apr 15, 2014
Publicly Available Date Apr 15, 2014
Journal Journal of Physiology
Print ISSN 0022-3751
Electronic ISSN 0022-3751
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 591
Issue 11
Public URL
Publisher URL


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