PMID- 32013718
OWN - NLM
STAT- MEDLINE
DCOM- 20211203
LR  - 20240226
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 17
IP  - 3
DP  - 2021 Mar
TI  - Long-lived mice with reduced growth hormone signaling have a constitutive 
      upregulation of hepatic chaperone-mediated autophagy.
PG  - 612-625
LID - 10.1080/15548627.2020.1725378 [doi]
AB  - Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal 
      proteolysis. CMA modulates proteomic organization through selective protein 
      degradation, with targets including metabolic enzymes, cell growth regulators, 
      and neurodegeneration-related proteins. CMA activity is low in ad libitum-fed 
      rodents but is increased by prolonged fasting. AKT negatively regulates CMA at 
      the lysosomal membrane by phosphorylating and inhibiting the CMA regulator GFAP. 
      We have previously reported that long-lived Pou1f1/Pit1 mutant (Snell) mice and 
      ghr (growth hormone receptor) knockout mice (ghr KO) have lower AKT activity when 
      fed compared to littermate controls, suggesting the hypothesis that these mice 
      have increased baseline CMA activity. Here, we report that liver lysosomes from 
      fed Snell dwarf mice and ghr KO mice have decreased GFAP phosphorylation and 
      increased CMA substrate uptake activity. Liver lysosomes isolated from fed Snell 
      dwarf mice and ghr KO mice injected with the protease inhibitor leupeptin had 
      increased accumulation of endogenous CMA substrates, compared to littermate 
      controls, suggesting an increase in CMA in vivo. Mice with liver-specific 
      ablation of GH (growth hormone) signaling did not have increased liver CMA, 
      suggesting that a signaling effect resulting from a loss of growth hormone in 
      another tissue causes enhanced CMA in Snell dwarf and ghr KO mice. Finally, we 
      find Snell dwarf mice have decreased protein levels (in liver and kidney) of 
      CIP2A, a well-characterized CMA target protein, without an associated change in 
      Cip2a mRNA. Collectively, these data suggest that CMA is enhanced downstream of 
      an endocrine change resulting from whole-body ablation of GH 
      signaling.Abbreviations: CMA: chaperone-mediated autophagy; GH: growth hormone; 
      ghr KO: growth hormone receptor knockout; LAMP2A: splice variant 1 of Lamp2 
      transcript; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; Li-ghr KO: 
      liver-specific ghr knockout; MA: macroautophagy; MTORC1: mechanistic target of 
      rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase 
      complex 2; PBS: phosphate-buffered saline.
FAU - Endicott, S Joseph
AU  - Endicott SJ
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 
      USA.
FAU - Boynton, Dennis N Jr
AU  - Boynton DN Jr
AD  - College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, 
      MI, USA.
FAU - Beckmann, Logan J
AU  - Beckmann LJ
AD  - College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, 
      MI, USA.
FAU - Miller, Richard A
AU  - Miller RA
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 
      USA.
AD  - Institute of Gerontology, University of Michigan Geriatrics Center, Ann Arbor, 
      MI, USA.
LA  - eng
GR  - T32 AG000114/AG/NIA NIH HHS/United States
GR  - U19 AG023122/AG/NIA NIH HHS/United States
GR  - UH3 AG064706/AG/NIA NIH HHS/United States
GR  - UH2 AG064706/AG/NIA NIH HHS/United States
GR  - U01 AG022303/AG/NIA NIH HHS/United States
GR  - P30 AG024824/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200212
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 9002-72-6 (Growth Hormone)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
SB  - IM
MH  - Animals
MH  - Chaperone-Mediated Autophagy/*genetics/physiology
MH  - Growth Hormone/*metabolism
MH  - Liver/metabolism
MH  - Lysosomes/*metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/metabolism
MH  - Mice, Knockout
MH  - Signal Transduction/*genetics/physiology
MH  - Mice
PMC - PMC8032237
OTO - NOTNLM
OT  - Aging
OT  - chaperone-mediated autophagy
OT  - endocrine control of autophagy
OT  - endocrine signaling
OT  - growth hormone
COIS- No potential conflict of interest was reported by the authors.
EDAT- 2020/02/06 06:00
MHDA- 2021/12/15 06:00
PMCR- 2021/02/12
CRDT- 2020/02/05 06:00
PHST- 2020/02/06 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2020/02/05 06:00 [entrez]
PHST- 2021/02/12 00:00 [pmc-release]
AID - 1725378 [pii]
AID - 10.1080/15548627.2020.1725378 [doi]
PST - ppublish
SO  - Autophagy. 2021 Mar;17(3):612-625. doi: 10.1080/15548627.2020.1725378. Epub 2020 
      Feb 12.