Perspective: The Potential Role of Essential Amino Acids and the Mechanistic Target of Rapamycin Complex 1 (mTORC1) Pathway in the Pathogenesis of Child Stunting

Abstract

Stunting is the best summary measure of chronic malnutrition in children. Approximately one-quarter of children under age 5 worldwide are stunted. Lipid-based or micronutrient supplementation has little to no impact in reducing stunting, which suggests that other critical dietary nutrients are missing. A dietary pattern of poor-quality protein is associated with stunting. Stunted children have significantly lower circulating essential amino acids than do nonstunted children. Inadequate dietary intakes of essential amino acids could adversely affect growth, because amino acids are required for synthesis of proteins. The master growth regulation pathway, the mechanistic target of rapamycin complex 1 (mTORC1) pathway, is exquisitely sensitive to amino acid availability. mTORC1 integrates cues such as nutrients, growth factors, oxygen, and energy to regulate growth of bone, skeletal muscle, nervous system, gastrointestinal tract, hematopoietic cells, immune effector cells, organ size, and whole-body energy balance. mTORC1 represses protein and lipid synthesis and cell and organismal growth when amino acids are deficient. Over the past 4 decades, the main paradigm for child nutrition in developing countries has been micronutrient malnutrition, with relatively less attention paid to protein. In this Perspective, we present the view that essential amino acids and the mTORC1 pathway play a key role in child growth. The current assumption that total dietary protein intake is adequate for growth among most children in developing countries needs re-evaluation.

Keywords: amino acids; children; diet; food; growth; mTORC1; proteins; stunting.

Conflict of interest statement

3 Author disclosures: RD Semba, I Trehan, M Gonzalez-Freire, K Kraemer, R Moaddel, MI Ordiz, L Ferrucci, and MJ Manary, no conflicts of interest.

© 2016 American Society for Nutrition.

Figures

FIGURE 1

The mTORC1 amino acid–sensing pathway. (A) With sufficient amino acids, GATOR1 is inhibited by GATOR2. Ragulator and v-ATPase undergo a conformation change. GEF activity is promoted by Ragulator toward RagA. Folliculin promotes GAP activity toward RagC, causing GTP hydrolysis. The active RagA/BGTP-RagC/DGDP heterodimers recruit mTORC1 to the lysosomal membrane. At the lysosomal surface, mTORC1 is activated by Rheb. ARF1 is involved in Rag GTPase-independent signaling to mTORC1. (B) With amino acid deficiency, GATOR1 inhibits RagA by exerting GAP activity. Both Sestrin2 and CASTOR1 interact with GATOR2, removing inhibition of GATOR2 on GATOR1. TSC inhibits Rheb through GAP activity. Ragulator is in an inhibitory state with v-ATPase. mTORC1 remains inactive in the cytoplasm. ARF1, ADP-ribosylation factor 1; GAP, GTPase-activating protein; GATOR, GAP activity towards Rags (Ras-related GTPases) GEF, guanine nucleotide exchange factor; mTORC1, mechanistic target of rapamycin complex 1; Rag, Ras-related GTP-binding protein; Rheb, Ras homolog enriched in brain; SLC38A9, solute carrier family 38, member 9; TSC, tuberous sclerosis complex; v-ATPase, vacuolar H+-ATPase.

FIGURE 2

GCN2 pathway of amino–acid sensing and interaction with mTORC1. GCN2 specifically recognizes “uncharged” tRNAs not covalently bound to cognate amino acids. With amino acid deficiency, uncharged tRNAs accumulate and bind to GCN2. GCN2 then phosphorylates (P) and inhibits eIFα2 and protein synthesis. Studies have shown that amino acid deficiency can inhibit mTORC1, either through ATF4 and Sestrin2 or independent of these 2 mediators. Inhibition of mTORC1 represses protein and lipid synthesis and promotes autophagy. ATF4, activating transcription factor 4; eIFα2, eukaryotic translation initiation factor 2α GCN2, general control non-derepressible 2; mTORC1, mechanistic target of rapamycin complex 1; tRNA, transfer RNA.