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Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37 Page 9

[253]
enhanced the expression of glucose-regulated protein 94 (GRP94) , the most abundant intraluminal
endoplasmic reticulum chaperone that aids in the synthesis of IGF-1, IGF-2, and proinsulin [254,255] .

IGF-1 activates the PI3K-AKT pathway. Activated AKT phosphorylates tuberin (TSC2), which promotes
the dissociation of TSC2 from the lysosomal membrane activating RAS homolog enriched in brain (RHEB).
RHEB finally activates mTORC1 at the lysosomal membrane [207,210,256-260] . IGF-1 is a pivotal promoter of linear
growth and body size [261-265] .

Milk protein-derived insulinotropic BCAAs are released by intestinal hydrolysis. They induce postprandial
hyperinsulinemia explaining milk’s high insulinemic index compared to its low glycemic index [266,267] . Fast
intestinal hydrolysis of whey protein-derived amino acids contributes to milk’s high insulinemic
effect [236,268-271] . In a synergistic fashion, insulin and IGF-1 activate PI3K-AKT-mTORC1 signaling and
thereby promote growth and anabolism of target tissues [257,259,272-276] .

Amino acids
Compared to other protein sources, milk protein and casein contain high amounts leucine and methionine.
Compared to meat, whey proteins are highly enriched in leucine [47,277] . In addition, milk protein exhibits a
[278]
high glutamine content (8.1 g/100 g protein) compared to beef (glutamine 4.75 g/100 g protein) .
Glutamine via the glutaminolysis pathway also results in mTORC1 activation [279,280] . Major milk-derived
amino acids such as leucine, arginine, and methionine are sensed via sestrin 2, cellular arginine sensor for
mTORC1, and S-adenosylmethionine sensor upstream of mTOR, respectively. These amino acids stimulate
mTORC1 activation through RAG GTPase pathways [281-298] . Glutamine activates mTORC1 through a RAG
[297]
GTPase-independent mechanism that requires ADP-ribosylation factor 1 (ARF1) . Leucyl-tRNA
synthetase (LRS) is another amino acid-dependent regulator of mTORC1 [299,300] . LRS senses intracellular
leucine concentration and directly binds to RAG GTPase, the mediator of amino acid signaling to
mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein for RAG
[300]
GTPase to activate mTORC1 . Moreover, LRS operates as a leucine sensor for the activation of the class
III PI3K Vps34 that mediates amino acid signaling to mTORC1 by regulating lysosomal translocation and
[301]
activation of the phospholipase PLD1 . mTORC1 activation involves leucine sensing, LRS translocation to
the lysosome, and interaction with RAGD [302-305] . There is a further function of LRS1 in glucose-dependent
[306]
control of leucine usage . Upon glucose starvation, LRS1 is phosphorylated by Unc-51-like autophagy
activating kinase 1 at the residues crucial for leucine binding. Phosphorylated LRS1 decreases leucine
binding, which may inhibit protein synthesis thereby saving energy .
[306]

In addition, arginine relieves allosteric inhibition of RHEB by TSC . Arginine cooperates with growth
[307]
factor signaling, which further dissociates TSC2 from lysosomes and activates of mTORC1 .
[307]
Taken together, full mTORC1 activation only occurs when both RAG and RHEB GTPase pathways are fully
activated, neither being sufficient alone . The final activators of growth factor and amino acids signaling
[295]
pathways, RHEB and RAGs, converge at the lysosome to activate mTORC1 [Figure 2] [281-296,308] .

Palmitic acid
The predominant saturated fatty acid of milk triacylglycerols (TAGs) is palmitic acid (C16:0), which is
[311]
transported in milk fat globules (MFGs) [309,310] ; MFGs, in turn, transfer energy through their TAG core .
After intestinal TAG hydrolysis and re-esterification into chylomicrons, palmitic acid serves as an energy
source and fuels mitochondrial β-oxidation for ATP synthesis [312,313] . ATP inhibits AMP-activated protein
kinase (AMPK) and thereby activates mTORC1 [314-316] . As shown in skeletal muscle cells, palmitate activates