PMID- 30909319
OWN - NLM
STAT- MEDLINE
DCOM- 20200626
LR  - 20211204
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 18
IP  - 3
DP  - 2019 Jun
TI  - SLC1A5 glutamine transporter is a target of MYC and mediates reduced mTORC1 
      signaling and increased fatty acid oxidation in long-lived Myc hypomorphic mice.
PG  - e12947
LID - 10.1111/acel.12947 [doi]
LID - e12947
AB  - Mice that express reduced levels of the c-Myc gene (Myc(+/-) heterozygotes) are 
      long-lived. Myc hypomorphic mice display reduced rates of protein translation and 
      decreased activity of the mammalian target of rapamycin (mTOR) complex 1 
      (mTORC1). Given the prominent effect of mTOR on aging, lower mTORC1 activity 
      could contribute to the exceptional longevity and enhanced healthspan of Myc(+/-) 
      animals. However, given the downstream position of MYC in these signaling 
      cascades, the mechanism through which mTORC1 activity is downregulated in 
      Myc(+/-) mice is not understood. We report that the high-affinity glutamine 
      transporter SLC1A5, which is critical for activation of mTORC1 activity by amino 
      acids, is a transcriptional target of MYC. Myc(+/-) cells display decreased 
      Slc1a5 gene expression that leads to lower glutamine uptake and consequently 
      reduced mTORC1 activity. Decreased mTORC1 activity in turn mediates an elevation 
      of fatty acid oxidation (FAO) by indirectly upregulating the expression of 
      carnitine palmitoyltransferase 1a (Cpt1a) that mediates the rate-limiting step of 
      beta-oxidation. Increased FAO has been noted in a number of long-lived mouse models. 
      Taken together, our results show that transcriptional feedback loops regulated by 
      MYC modulate upstream signaling pathways such as mTOR and impact FAO on an 
      organismal level.
CI  - (c) 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley 
      & Sons Ltd.
FAU - Zhao, Xiaoai
AU  - Zhao X
AD  - Department of Molecular Biology, Cell Biology and Biochemistry, and Center on the 
      Biology of Aging, Brown University, Providence, Rhode Island.
FAU - Petrashen, Anna P
AU  - Petrashen AP
AD  - Department of Molecular Biology, Cell Biology and Biochemistry, and Center on the 
      Biology of Aging, Brown University, Providence, Rhode Island.
FAU - Sanders, Jennifer A
AU  - Sanders JA
AD  - Department of Pediatrics, Rhode Island Hospital and Brown University, Providence, 
      Rhode Island.
FAU - Peterson, Abigail L
AU  - Peterson AL
AD  - Department of Molecular Biology, Cell Biology and Biochemistry, and Center on the 
      Biology of Aging, Brown University, Providence, Rhode Island.
FAU - Sedivy, John M
AU  - Sedivy JM
AUID- ORCID: 0000-0001-9363-4253
AD  - Department of Molecular Biology, Cell Biology and Biochemistry, and Center on the 
      Biology of Aging, Brown University, Providence, Rhode Island.
LA  - eng
GR  - R37 AG016694/AG/NIA NIH HHS/United States
GR  - R61 AR076807/AR/NIAMS NIH HHS/United States
GR  - T32 AG041688/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190325
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - 0 (Amino Acid Transport System ASC)
RN  - 0 (Fatty Acids)
RN  - 0 (Minor Histocompatibility Antigens)
RN  - 0 (Myc protein, mouse)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Slc1a5 protein, mouse)
RN  - 0RH81L854J (Glutamine)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amino Acid Transport System ASC/genetics/*metabolism
MH  - Animals
MH  - Carnitine O-Palmitoyltransferase/genetics/metabolism
MH  - Cell Line
MH  - Fatty Acids/metabolism
MH  - Glutamine/*metabolism
MH  - Hepatocytes/enzymology/metabolism
MH  - Longevity/*genetics
MH  - Mechanistic Target of Rapamycin Complex 1/*metabolism
MH  - Mice
MH  - Minor Histocompatibility Antigens/genetics/*metabolism
MH  - Oxidation-Reduction
MH  - Protein Biosynthesis/genetics
MH  - Proto-Oncogene Proteins c-myc/genetics/*metabolism
MH  - Signal Transduction/genetics
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
PMC - PMC6516164
OTO - NOTNLM
OT  - MYC gene
OT  - fatty acid oxidation
OT  - genetic models
OT  - mTOR signaling
OT  - metabolic regulation
OT  - mouse longevity
COIS- None declared.
EDAT- 2019/03/26 06:00
MHDA- 2020/06/27 06:00
PMCR- 2019/06/01
CRDT- 2019/03/26 06:00
PHST- 2018/08/17 00:00 [received]
PHST- 2019/01/11 00:00 [revised]
PHST- 2019/03/01 00:00 [accepted]
PHST- 2019/03/26 06:00 [pubmed]
PHST- 2020/06/27 06:00 [medline]
PHST- 2019/03/26 06:00 [entrez]
PHST- 2019/06/01 00:00 [pmc-release]
AID - ACEL12947 [pii]
AID - 10.1111/acel.12947 [doi]
PST - ppublish
SO  - Aging Cell. 2019 Jun;18(3):e12947. doi: 10.1111/acel.12947. Epub 2019 Mar 25.