Leucine and mTORC1: a complex relationship

2012 ◽  
Vol 302 (11) ◽  
pp. E1329-E1342 ◽  
Author(s):  
Kayleigh M. Dodd ◽  
Andrew R. Tee
Keyword(s):  
Signal Transduction ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Protein Turnover ◽  
Muscle Growth ◽  
Protein Translation ◽  
Amino Acid Availability ◽  
Intracellular Amino Acid ◽  
System L ◽  
Mtorc1 Signaling

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.

Human muscle protein synthesis and breakdown during and after exercise

2009 ◽  
Vol 106 (6) ◽  
pp. 2026-2039 ◽  
Author(s):  
Vinod Kumar ◽  
Philip Atherton ◽  
Kenneth Smith ◽  
Michael J. Rennie
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Protein Turnover ◽  
Acute Exercise ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mitochondrial Protein ◽  
Human Muscle ◽  
Muscle Protein Turnover ◽  
Amino Acid Availability

Skeletal muscle demonstrates extraordinary mutability in its responses to exercise of different modes, intensity, and duration, which must involve alterations of muscle protein turnover, both acutely and chronically. Here, we bring together information on the alterations in the rates of synthesis and degradation of human muscle protein by different types of exercise and the influences of nutrition, age, and sexual dimorphism. Where possible, we summarize the likely changes in activity of signaling proteins associated with control of protein turnover. Exercise of both the resistance and nonresistance types appears to depress muscle protein synthesis (MPS), whereas muscle protein breakdown (MPB) probably remains unchanged during exercise. However, both MPS and MPB are elevated after exercise in the fasted state, when net muscle protein balance remains negative. Positive net balance is achieved only when amino acid availability is increased, thereby raising MPS markedly. However, postexercise-increased amino acid availability is less important for inhibiting MPB than insulin, the secretion of which is stimulated most by glucose availability, without itself stimulating MPS. Exercise training appears to increase basal muscle protein turnover, with differential responses of the myofibrillar and mitochondrial protein fractions to acute exercise in the trained state. Aging reduces the responses of myofibrillar protein and anabolic signaling to resistance exercise. There appear to be few, if any, differences in the response of young women and young men to acute exercise, although there are indications that, in older women, the responses may be blunted more than in older men.

Protein turnover and amino acid transport kinetics in end-stage renal disease

2004 ◽  
Vol 286 (1) ◽  
pp. E136-E143 ◽  
Author(s):  
Dominic S. C. Raj ◽  
Philip Zager ◽  
Vallbh O. Shah ◽  
Elizabeth A. Dominic ◽  
Oladipo Adeniyi ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Amino Acid Transport ◽  
Protein Turnover ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Transport Kinetics ◽  
Acid Transport ◽  
Intracellular Amino Acid ◽  
Stage Renal Disease

Protein and amino acid metabolism is abnormal in end-stage renal disease (ESRD). Protein turnover is influenced by transmembrane amino acid transport. The effect of ESRD and hemodialysis (HD) on intracellular amino acid transport kinetics is unknown. We studied intracellular amino acid transport kinetics and protein turnover by use of stable isotopes of phenylalanine, leucine, lysine, alanine, and glutamine before and during HD in six ESRD patients. Data obtained from amino acid concentrations and enrichment in the artery, vein, and muscle compartments were used to calculate intracellular amino acid transport and muscle protein synthesis and catabolism. Fractional muscle protein synthesis (FSR) was estimated by the precursor product approach. Despite a significant decrease in the plasma concentrations of amino acids in the artery and vein during HD, the intracellular concentrations remained stable. Outward transport of the amino acids was significantly higher than the inward transport during HD. FSR increased during HD (0.0521 ± 0.0043 vs. 0.0772 ± 0.0055%/h, P < 0.01). Results derived from compartmental modeling indicated that both protein synthesis (118.3 ± 20.6 vs. 146.5 ± 20.6 nmol·min-1·100 ml leg-1, P < 0.01) and catabolism (119.8 ± 18.0 vs. 174.0 ± 14.2 nmol·min-1·100 ml leg-1, P < 0.01) increased during HD. However, the intradialytic increase in catabolism exceeded that of synthesis (57.8 ± 13.8 vs. 28.0 ± 8.5%, P < 0.05). Thus HD alters amino acid transport kinetics and increases protein turnover, with net increase in protein catabolism.

scholarly journals Stimulation of Muscle Protein Synthesis by Prolonged Parenteral Infusion of Leucine Is Dependent on Amino Acid Availability in Neonatal Pigs

2009 ◽  
Vol 140 (2) ◽  
pp. 264-270 ◽  
Author(s):  
Fiona A. Wilson ◽  
Agus Suryawan ◽  
Maria C. Gazzaneo ◽  
Renán A. Orellana ◽  
Hanh V. Nguyen ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Neonatal Pigs ◽  
Amino Acid Availability ◽  
Stimulation Of

AMINO ACID UTILIZATION AND PROTEIN SYNTHESIS IN THE OVINE FETUS IN UTERO

1984 ◽  
Vol 64 (5) ◽  
pp. 287-288 ◽  
Author(s):  
D. D. KITTS ◽  
A. L. SCHAEFER ◽  
C. R. KRISHNAMURTI
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Key Words ◽  
Protein Turnover ◽  
In Utero ◽  
Intermediary Metabolites ◽  
Tissue Protein ◽  
Amino Acid Utilization ◽  
Ovine Fetus

The utilization of amino acids in chronically catheterized ovine fetuses was measured by isotopic and nonisotopic procedures. Extensive incorporation of amino acid carbon into tissue protein was accompanied by high protein turnover and recycling rates of amino acid carbon. Alternative utilization of amino acids included oxidation and conversion into intermediary metabolites. Key words: Amino acids, utilization, fetus

scholarly journals PROTEIN METABOLISM IN TUMOR CELLS AT VARIOUS STAGES OF GROWTH IN VIVO

1974 ◽  
Vol 62 (3) ◽  
pp. 585-593 ◽  
Author(s):  
Massimo Olivotto ◽  
Francesco Paoletti
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Tumor Cells ◽  
Protein Metabolism ◽  
Protein Turnover ◽  
Specific Activity ◽  
Cell Mass ◽  
Ascites Hepatoma ◽  
Two Phases

Protein metabolism of Yoshida ascites hepatoma cells was studied in the early phase of logarithmic proliferation and in the following stage in which cell mass remains constant (resting phase). The rate of protein synthesis was measured by a short-time incorporation of [8H]lysine, while degradation was concurrently assessed by following the decrease of specific activity of [14C]lysine-labeled proteins. Most of the labeled amino acid injected intraperitoneally into the animal was immediately available for the tumor cells, with only a minor loss towards the extra-ascitic compartment. It was thus possible to calculate the dilution of the isotope in the ascitic pool of the lysine, which increased concurrently with the ascitic plasma volume. Amino acid transport capacity did not change in the log vs. the resting cells. This fact permitted the correction of the specific activity of the proteins synthesized by tumors in the two phases, taking into account the dilution effect. Protein synthesis was found to proceed at a constant rate throughout each of the two phases, although it was 30% lower during the resting as compared to the log phase. When cell mass attained the steady-state, protein degradation occurred at such a level as to balance the synthesis. Throughout the resting phase the amount of lysine taken up by the cells and renewed from the blood remained unchanged. Protein turnover, as studied in subcellular fractions, exhibited a similar rate in nuclei and microsomes, where it proceeded at a higher level than in mitochondria. On the whole, the results encourage the use of the Yoshida ascites hepatoma as a suitable model for studying protein turnover in relation to cell growth in vivo.

Control of Muscle Protein Synthesis as a Result of Contractile Activity and Amino Acid Availability: Implications for Protein Requirements

2001 ◽  
Vol 11 (s1) ◽  
pp. S170-S176 ◽  
Author(s):  
Michael J. Rennie
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Muscle Protein ◽  
Contractile Activity ◽  
Muscle Protein Synthesis ◽  
Protein Requirements ◽  
Amino Acid Availability ◽  
Separate Pathway

The major anabolic influences on muscle are feeding and contractile activity. As a result of feeding, anabolism occurs chiefly by increases in protein synthesis with minor changes in protein breakdown. Insulin has a permissive role in increasing synthesis, but the availability of amino acids is crucial for net anabolism. We have investigated the role of amino acids in stimulating muscle protein synthesis, the synergy between exercise and amino acid availability, and some of the signaling elements involved. The results suggest that muscle is acutely sensitive to amino acids, that exercise probably increases the anabolic effects of amino acids by a separate pathway, and that for this reason it is unlikely that accustomed physical exercise increases protein requirements.

scholarly journals Short translational ramp determines efficiency of protein synthesis

2019 ◽  
Author(s):  
Manasvi Verma ◽  
Junhong Choi ◽  
Kyle A. Cottrell ◽  
Zeno Lavagnino ◽  
Erica N. Thomas ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Amino Acid Sequence ◽  
Single Molecule ◽  
Translation Initiation ◽  
Protein Translation ◽  
Translational Efficiency ◽  
Translation Efficiency ◽  
Sequence Motifs ◽  
Peptide Bond Formation

AbstractIt is generally assumed that translation efficiency is governed by translation initiation. However, the efficiency of protein synthesis is regulated by multiple factors including tRNA abundance, codon composition, mRNA motifs and amino-acid sequence1–4. These factors influence the rate of protein synthesis beyond the initiation phase of translation, typically by modulating the rate of peptide-bond formation and to a lesser extent that of translocation. The slowdown in translation during the early elongation phase, known as the 5’ translational ramp, likely contributes to the efficiency of protein synthesis 5–9. Multiple mechanisms, which could explain the molecular basis for this translational ramp, have been proposed that include tRNA abundance bias6,9, the rate of translation initiation10–15, mRNA and ribosome structure 11,12,14,16–18, or retention of initiation factors during early elongation events 19. Here, we show that the amount of synthesized protein (translation efficiency) depends on a short translational ramp that comprises the first 5 codons in mRNA. Using a library of more than 250,000 reporter sequences combined with in vitro and in vivo protein expression assays, we show that differences in the short ramp can lead to 3 to 4 orders of magnitude changes in protein abundance. The observed difference is not dependent on tRNA abundance, efficiency of translation initiation, or overall mRNA structure. Instead, we show that translation is regulated by amino-acid-sequence composition and local mRNA sequence. Single-molecule measurements of translation kinetics indicate substantial pausing of ribosome and abortion of protein synthesis on the 4th or 5th codon for distinct amino acid or nucleotide compositions. Introduction of preferred sequence motifs, only at the exact positions within the mRNA, improves protein synthesis for recombinant proteins, indicating an evolutionarily conserved mechanism for controlling translational efficiency.

scholarly journals Cancer‐secreted miRNAs regulate amino‐acid‐induced mTORC1 signaling and fibroblast protein synthesis

EMBO Reports ◽  
2020 ◽  
Author(s):  
Miranda Y Fong ◽  
Wei Yan ◽  
Majid Ghassemian ◽  
Xiwei Wu ◽  
Xin Zhou ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Mtorc1 Signaling
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