Leucine and mTORC1: a complex relationship

Abstract

Amino acid availability is a rate-limiting factor in the regulation of protein synthesis. When amino acid supplies become restricted, mammalian cells employ homeostatic mechanisms to rapidly inhibit processes such as protein synthesis, which demands high levels of amino acids. Muscle cells in particular are subject to high protein turnover rates to maintain amino acid homeostasis. Mammalian target of rapamycin complex 1 (mTORC1) is an evolutionary conserved multiprotein complex that coordinates a network of signaling cascades and functions as a key mediator of protein translation, gene transcription, and autophagy. Signal transduction through mTORC1, which is centrally involved in muscle growth through enhanced protein translation, is governed by intracellular amino acid supply. The branched-chain amino acid leucine is critical for muscle growth and acts in part through activation of mTORC1. Recent research has revealed that mTORC1 signaling is coordinated primarily at the lysosomal membranes. This discovery has sparked a wealth of research in this field, revealing several different signaling molecules involved in transducing the amino acid signal to mTORC1, including the Rag GTPases, MAP4K3, and Vps34/ULK1. This review evaluates the current knowledge regarding cellular mechanisms that control and sense the intracellular amino acid pool. We discuss the role of leucine and mTORC1 in the regulation of amino acid transport via the system L and system A transporters such as LAT1 and SNAT2, as well as protein degradation via autophagic and proteasomal pathways. We also describe the complexities of energy homeostasis via AMPK and cell receptor-mediated growth signals that also converge on mTORC1. Leucine is a particularly potent regulator of protein turnover, to the extent where leucine stimulation alone is sufficient to stimulate mTORC1 signal transduction. The significance of leucine in this context is not yet known; however, recent advancements in this area will also be covered within this review.

Determination of Selected Amino Acids in Serum of Patients with Liver Disease

“…Therefore, patients with diabetes mellitus were excluded from the study. Insulin resistance results in increased proteolysis and BCAA levels are elevated [15,22]. In skeletal muscle, BCAAs act as an essential donor of nitrogen in the BCAA transaminase reaction to form glutamate.…”

“…Also worth mentioning is a positive correlation between BCAA and TG. It is known that BCAAs contribute to insulin resistance [22]. Insulin resistance may lead to an increase of serum TG.…”

New strategies in sport nutrition to increase exercise performance

“…Furthermore, mTORC1 has a number of repressors, which must be dissociated from the complex to allow it to become active, such as PRAS40 and DEPTOR [94]. Finally the amino acid sensitive lipid kinase hVPS34 also plays a key role in mTORC1 activation [95] as does the MAPK family member MAP4K3 [96] ( Figure 2). Cell based work has shown that this amino acid sensing system is incredibly sensitive with an ~7% increase in intracellular leucine leading to 50% maximal activation of mTORC1 [97].…”

Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

“…It has been previously reported that leucine can enhance mTORC1 (Deldicque et al 2008;Dodd and Tee 2012;Suryawan et al 2012;Xu et al 2013). To examine if the mTORC1 inhibitory effect of glutamine can be neutralized by coadministration of leucine in vivo, independent groups of rats were infused with leucine (27 mg) targeted to one hippocampus while Glutamine impairs long-term memory www.learnmem.org an equal volume of vehicle was simultaneously infused into the contralateral hippocampus.…”