Review Leucine as a treatment for muscle wasting: A critical review Daniel J. Ham, Marissa K. Caldow, Gordon S. Lynch, Ren  e Koopman * Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria 3010, Australia article info Article history: Received 16 May 2014 Accepted 22 September 2014 Keywords: Protein synthesis Protein breakdown mTOR Amino acids summary Amino acids are potent modulators of protein turnover and skeletal muscle cells are highly sensitive to changes in amino acid availability. During amino acid abundance increased activity of mTORC1 drives protein synthesis and growth. In skeletal muscle, it has been clearly demonstrated that of all the amino acids, leucine is the most potent stimulator of mTORC1 and protein synthesis in vitro and in vivo. As such, leucine has received considerable attention as a potential pharmaconutrient for the treatment of numerous muscle wasting conditions. However, despite a multitude of studies showing enhanced acute protein synthesis with leucine or leucine-rich supplements in healthy individuals, additional leucine intake does not necessarily enhance protein synthesis during muscle wasting conditions. In addition, long-term, placebo controlled, iso-caloric studies in humans consistently show no beneficial effect of leucine supplementation on skeletal muscle mass or function. This review, critically evaluates the therapeutic potential of leucine to attenuate the skeletal muscle wasting associated with ageing, cancer and immobilization/bed rest. It also highlights the impact of inflammation on amino acid sensing, mTORC1 activation and stimulation of protein synthesis and challenges the underlying hypothesis that the acute activation of mTORC1 and stimulation of protein synthesis by leucine increases in muscle mass over time. We conclude that leucine, as a standalone nutritional intervention, is not effective in the prevention of muscle wasting. Future work should focus on identifying and utilizing other nutrients or treatments that sensitize skeletal muscle to leucine, thereby enhancing its therapeutic potential for muscle wasting conditions. © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. 1. Introduction Skeletal muscle mass is determined by the balance between protein synthesis and protein degradation. Skeletal muscle mass is increased (muscle grows or hypertrophies) when a chronic alter- ation in this balance favors protein synthesis. Conversely, skeletal muscle wasting (loss of muscle or atrophy), occurs when protein degradation exceeds protein synthesis [1]. Muscle wasting is a serious complication of a wide range of diseases and conditions such as ageing, disuse, muscular dystrophy, chronic heart failure, sepsis, and many cancers [2], which impairs the quality of life of those affected. The mechanistic target of rapamycin (mTOR) plays a central role in regulating the balance between protein synthesis and protein breakdown and is therefore important for controlling skeletal muscle hypertrophy and atrophy. mTOR is a master regulator of cell size; integrating signals from nutrients (e.g. amino acids), growth factors (e.g. insulin & IGF-I), energy status (ATP) and stress to drive cell growth or activate energy sparing processes (for a more detailed review see [3,4]). Nutrients are the dominant input, since amino acids are both necessary and sufficient for mTOR activation. mTOR exists as two protein complexes, mTOR complex 1 (mTORC1) containing raptor and mTORC2 containing rictor. mTORC1 is rapamycin-sensitive, activated by amino acids and considered the master regulator of protein synthesis. Upon activation, mTORC1 phosphorylates and activates two parallel signaling pathways involved in the control of translation. S6 kinase 1 (S6K1) phos- phorylation leads to activation of the ribosomal protein S6, while phosphorylation of the eukaryotic initiation factor 4E (eIF4E)- binding protein (4EBP1) releases its inhibition of the translation initiation factor eIF-4E, allowing initiation of translation and the synthesis of new proteins (Fig. 1). Growth factors stimulate mTORC1 by a well-defined mechanism involving the phosphorylation of Akt which leads to the phos- phorylation and subsequent inhibition of both tuberous sclerosis complex protein 2 (TSC2) and the proline-rich Akt substrate 40 kDa (PRAS40), allowing the small GTPase Ras homolog enriched in brain (Rheb) to bind to mTORC1 and promote its kinase activity. How- ever, growth factors cannot efficiently activate mTORC1 without * Corresponding author. Tel.: þ61 3 8344 0243; fax: þ61 3 8344 5818. E-mail address: rkoopman@unimelb.edu.au (R. Koopman). Contents lists available at ScienceDirect Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu http://dx.doi.org/10.1016/j.clnu.2014.09.016 0261-5614/© 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. Clinical Nutrition xxx (2014) 1e9 Please cite this article in press as: Ham DJ, et al., Leucine as a treatment for muscle wasting: A critical review, Clinical Nutrition (2014), http:// dx.doi.org/10.1016/j.clnu.2014.09.016