Symposium on branched-chain amino acids: conference summary.

BCAAs, especially leucine, were shown in the mid-1970s to be potent regulators of protein turnover (1–3). In the mid1980s BCAAs were also shown to compete with other large neutral amino acids (LNAAs) (4), suggesting that raising the blood concentration of BCAA would limit the formation of false neurotransmitters within the brain. Although these findings would seem to have provided an attractive basis for BCAA supplementation in various physiological or pathological situations, they were not sufficient at that time because our understanding of in vivo metabolism and cell signaling were limited and no clear biomarkers of BCAA status were available (5). As a result, the idea that BCAA supplementation might have merit received limited attention but is now experiencing a major revival thanks to recent progress, as discussed by an enthusiastic group of participants at a conference held last May in Versailles, France. The conference was opened with the interesting question: Why is it that nature chose to have three BCAAs? Why not one, two, or some other number of BCAAs? Is something special obtained from the metabolism of each of the BCAAs? A strong case was presented for the importance of BCAAs in determining protein structure (6). Indeed, there is growing evidence that BCAAs play significantly different structural roles in proteins, even though only slight differences exist in their side chains. The fact that the catabolism of all three BCAAs is controlled at the common step catalyzed by the branched-chain ketoacid dehydrogenase complex (BCKDC) implies that the individual end products of BCAA catabolism do not have important functions. Understanding the mechanism of how BCAAs regulate protein synthesis and degradation requires an in-depth appreciation for how other factors affect these processes, particularly insulin, insulin-like growth factor-I (IGF-I), and growth hormone (GH) (7). Although often overlooked, vascular actions of these hormones impact the delivery of amino acids to skeletal muscle cells. Resting blood flow to skeletal muscle is slow but can increase greatly in response to exercise, insulin, IGF-I, and GH. These effects are due to vasodilation induced by nitric oxide stimulation of guanylyl cyclase in endothelial cells of the capillaries of the vasculature, an important component of the mechanisms by which GH, IGF-I, insulin, and amino acids promote muscle protein accretion. The brain content of BCAA is regulated by the transport properties of the capillary endothelial cells that form the blood– brain barrier (8). The polar distribution of transport proteins in the luminal (blood-facing) and abluminal (brain-facing) plasma membranes of the endothelium mediates amino acid homeostasis in the brain. The blood–brain barrier restricts the entry of glutamine and glutamate into the brain and actively exports these amino acids to the circulation to protect against glutamate and ammonia toxicity. The mechanism by which leucine regulates muscle-protein synthesis was a major theme of the conference. Upregulation of the initiation of mRNA translation via activation of the mammalian target of rapamycin (mTOR) signaling pathway is clearly involved (9). Several new signaling molecules have been identified recently that may be involved in mediating the effect of leucine on mTOR. Insulin-dependent and independent mechanisms are clearly involved in the mechanism of leucine action. Whether a receptor for leucine exists and whether a leucine metabolite is involved in the signaling mechanism are two of the many questions that remain to be answered. Major advances have been made recently in understanding the control of skeletal muscle protein degradation by the ubiquitin-proteosome pathway, the most important degradation system for proteins in mammalian cells (10). Most proteins in mammalian cells are degraded by this system. Genes that are expressed at a higher level in atrophying muscle are called atrogenes. These include genes encoding enzymes that tag protein substrates with ubiquitin for degradation by the proteosome. Glucocorticoids or lack of amino acids induce atrogenes and stimulate protein degradation. IGF-I and insulin suppress the expression of atrogenes and inhibit muscle proteolysis. The 1 Published in a supplement to The Journal of Nutrition. Presented at the conference ‘‘Symposium on Branched-Chain Amino Acids,’’ held May 23–24, 2005 in Versailles, France. The conference was sponsored by Ajinomoto USA, Inc. The organizing committee for the symposium and guest editors for the supplement were Luc Cynober, Robert A. Harris, Dennis M. Bier, John O. Holloszy, Sidney M. Morris, Jr., and Yoshiharu Shimomura. Guest editor disclosure: L. Cynober, R. A. Harris, D. M. Bier, J. O. Holloszy, S. M. Morris, Y. Shimomura: expenses for travel to BCAA meeting paid by Ajinomoto USA; D. M. Bier: consults for Ajinomoto USA; S. M. Morris: received compensation from Ajinomoto USA for organizing BCAA conference. 2 Author Disclosure: L. Cynober and R. A. Harris’s expenses for travel to BCAA meeting were paid by Ajinomoto USA. 3 To whom correspondence should be addressed. Email: solange.ngon@ htd.ap-hop-paris.fr. 4 Abbreviations used: BCKA, branched-chain keto acid; BCKDC, branchedchain ketoacid dehydrogenase complex; GH, growth hormone; IGF-I, insulin-like growth factor-I; LNAA, large neutral amino acid; MSUD, maple syrup urine disease; mTOR, mammalian target of rapamycin; Trp, tryptophan.