PMID- 27236753
OWN - NLM
STAT- MEDLINE
DCOM- 20170512
LR  - 20211204
IS  - 1525-3198 (Electronic)
IS  - 0022-0302 (Linking)
VI  - 99
IP  - 8
DP  - 2016 Aug
TI  - Development of a model describing regulation of casein synthesis by the mammalian 
      target of rapamycin (mTOR) signaling pathway in response to insulin, amino acids, 
      and acetate.
PG  - 6714-6736
LID - S0022-0302(16)30302-2 [pii]
LID - 10.3168/jds.2015-10591 [doi]
AB  - To improve dietary protein use efficiency in lactating cows, mammary protein 
      synthesis responses to AA, energy substrates, and hormones must be better 
      understood. These entities exert their effects through stimulation of mRNA 
      translation via control of initiation and elongation rates at the cellular level. 
      A central protein kinase of this phenomenon is the mammalian target of rapamycin 
      (mTOR), which transfers the nutritional and hormonal stimuli onto a series of 
      proteins downstream through a cascade of phosphorylation reactions that 
      ultimately affect protein synthesis. The objective of this work was to further 
      develop an existing mechanistic model of mTOR phosphorylation responses to 
      insulin and total essential AA to include the effects of specific essential AA 
      and acetate mediated by signaling proteins including protein kinase B (Akt), 
      adenosine monophosphate activated protein kinase (AMPK), and mTOR and to add a 
      representation of milk protein synthesis. Data from 6 experiments in MAC-T cells 
      and mammary tissue slices previously conducted in our laboratory were assembled 
      and used to parameterize the dynamic system of differential equations 
      representing Akt, AMPK, and mTOR in their phosphorylated and dephosphorylated 
      states and the resulting regulation of milk protein synthesis. The model 
      predicted phosphorylated Akt, mTOR, AMPK, and casein synthesis rates with root 
      mean square prediction errors of 16.8, 28.4, 33.0, and 54.9%, respectively. All 
      other dependent variables were free of mean and slope bias, indicating an 
      adequate representation of the data. Whereas mTOR was not very sensitive to 
      changes in insulin or acetate levels, it was highly sensitive to leucine and 
      isoleucine, and this signal appeared to be effectively transduced to casein 
      synthesis. Although prior work had observed a relationship with additional 
      essential AA, and data supporting those conclusions were present in the data set, 
      we were unable to derive significant relationships with any essential AA other 
      than leucine and isoleucine. The signaling properties and dynamics of AMPK under 
      nutrient depletion and sufficiency, the responses to additional essential AA, and 
      the consequent effects on protein synthesis remain to be better understood.
CI  - Copyright (c) 2016 American Dairy Science Association. Published by Elsevier Inc. 
      All rights reserved.
FAU - Castro, J J
AU  - Castro JJ
AD  - Department of Dairy Science, Virginia Tech, Blacksburg 24061. Electronic address: 
      cjuan3@vt.edu.
FAU - Arriola Apelo, S I
AU  - Arriola Apelo SI
AD  - Department of Dairy Science, Virginia Tech, Blacksburg 24061.
FAU - Appuhamy, J A D R N
AU  - Appuhamy JADRN
AD  - Department of Dairy Science, Virginia Tech, Blacksburg 24061.
FAU - Hanigan, M D
AU  - Hanigan MD
AD  - Department of Dairy Science, Virginia Tech, Blacksburg 24061.
LA  - eng
PT  - Journal Article
DEP - 20160526
PL  - United States
TA  - J Dairy Sci
JT  - Journal of dairy science
JID - 2985126R
RN  - 0 (Acetates)
RN  - 0 (Amino Acids)
RN  - 0 (Caseins)
RN  - 0 (Insulin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Acetates/metabolism
MH  - Amino Acids/*metabolism
MH  - Animals
MH  - Caseins/*metabolism
MH  - Cattle
MH  - Female
MH  - Insulin/metabolism
MH  - Lactation
MH  - Mammary Glands, Animal/metabolism
MH  - Phosphorylation
MH  - Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
OTO - NOTNLM
OT  - amino acids
OT  - casein
OT  - insulin
OT  - mTOR
EDAT- 2016/05/30 06:00
MHDA- 2017/05/13 06:00
CRDT- 2016/05/30 06:00
PHST- 2015/11/02 00:00 [received]
PHST- 2016/04/19 00:00 [accepted]
PHST- 2016/05/30 06:00 [entrez]
PHST- 2016/05/30 06:00 [pubmed]
PHST- 2017/05/13 06:00 [medline]
AID - S0022-0302(16)30302-2 [pii]
AID - 10.3168/jds.2015-10591 [doi]
PST - ppublish
SO  - J Dairy Sci. 2016 Aug;99(8):6714-6736. doi: 10.3168/jds.2015-10591. Epub 2016 May 
      26.