Essential amino acid sensing, signaling, and transport in the regulation of human muscle protein metabolism

Abstract

Purpose of review: To highlight the recent research pertaining to the cellular mechanisms linking amino acid availability, mTORC1 signaling, and muscle protein metabolism.

Recent findings: Activation of the mTORC1 pathway in response to amino acids may be dependent upon cellular relocalization of mTORC1, a process that appears to involve the Rag GTPases. Recent studies have also identified other intracellular proteins, such as hVps34 and MAP4K3, and specific amino acid transporters as necessary links between amino acid availability and mTORC1. In human skeletal muscle, it appears that mTORC1 activity increases the expression of several amino acid transporters, which may be an important adaptive response to sensitize muscle to a subsequent increase in amino acid availability.

Summary: The precise cellular mechanisms linking amino acids to mTORC1 signaling and muscle protein metabolism are currently not well understood. More defined cellular mechanisms are beginning to emerge suggesting a role for several intracellular proteins including hVps34, MAP4K3, and Rag GTPases. Additionally, specific amino acid transporters may have a role both upstream and downstream of mTORC1. Continued investigation into the precise cellular mechanisms linking amino acid availability and muscle protein metabolism will help facilitate improvements in existing therapies for conditions of muscle wasting.

Figures

Figure 1

Schematic of potential cellular mechanisms responsible for amino acid control of muscle protein synthesis. Gln, glutamine; BCAA, branch chain amino acids; RAG, Ras-related GTPase; PAT1, proton-assisted amino acid transporter 1; Akt, protein kinase B; mTORC1, mammalian target of rapamycin complex 1; Rab, member of the Rab family of GTPases; Rheb, ras-homologue enriched in brain; MAP4K3, mitogen activated protein kinase kinase kinase kinase-3; 4E-BP1, 4E binding protein 1; S6K1, p70 ribosomal S6 kinase 1; hVps34, human vacuolar protein sorting-34; eIF4F, eukaryotic initiation factor 4F; rpS6, ribosomal protein S6; eEF2, eukaryotic elongation factor 2.