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. 2023 Oct 6;20(1):2263409. doi: 10.1080/15502783.2023.2263409

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© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

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Figure 1b. — mTOR signaling: regulation of mTORC1 by upstream stimuli; insulin, exercise (resistance, endurance), glucose, and amino acids (Aa’s). Exercise leads to an energy deficit (increased AMP) stimulating AMPK, inhibiting mTORC1 whereas glucose consumption raises ATP, inhibiting AMPK. Insulin and resistance exercise activate the PI3K pathway, positively regulating mTORC1, while endurance exercise activates CaMK, mostly promoting mitochondrial biogenesis. AA’s primarily stimulate mTORC1 by promoting the phosphorylation and dephosphorylation of rag GTPases, rag A/B and rag C/D, respectively. AA’s generally stimulate FNIP1/FLCN, promoting dephosphorylation of rag C/D, however, some EAA’s (leucine, histidine, valine, threonine, isoleucine, methionine) act to promote phosphorylation of rag A/B; leading to an upregulation in mTORC1 and downstream translation as well as glucose and lipid metabolism. Figures are derived from [10–12].

Abbreviations: Akt, protein kinase B; AMPK, AMP-activated protein kinase; PI3K, phosphoinositide 3-kinase; Ca^{2 +}, calcium ion; CaMK, calcium/calmodulin-dependent protein kinase; FNIP1, folliculin-interacting protein 1; FLCN, folliculin (FLCN); mTORC1, mammalian target of rapamycin complex 1; FOX-O, forkhead box-O transcription factors; PGC-1α, peroxisome proliferator-activated gamma coactivator-1 alpha; MuRF-1, muscle ring-finger protein-1; eEF-2K, eukaryotic elongation factor-2 kinase; eEF2, eukaryotic elongation factor-2; TSC1/2, Tuberous sclerosis proteins 1 (hamartin) +2 (tuberin); Rheb, Ras homolog enriched in brain; LRS, leucyl-tRNA synthetase; SESN2, Sestrin-2; GATOR1/2, GAP (GTPase-activating protein) activity toward Rags 1+2; SAM, s-adenosyl methionine; SAMTOR, s-adenosyl methionine sensor for mTORC1; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; P70-S6K, (S6K1) ribosomal protein S6 kinase beta-1; SREBP, sterol regulatory element binding protein; HIF-1α, hypoxia-inducible factor-1 alpha; PDCD4, Programmed cell death protein 4; SKAR, S6K1 Aly/REF-like substrate; eIF4E/B, eukaryotic translation initiation factor 4E+B.