PMID- 27572850
OWN - NLM
STAT- MEDLINE
DCOM- 20170927
LR  - 20211204
IS  - 1554-527X (Electronic)
IS  - 0736-0266 (Print)
IS  - 0736-0266 (Linking)
VI  - 35
IP  - 7
DP  - 2017 Jul
TI  - mTOR signaling plays a critical role in the defects observed in muscle-derived 
      stem/progenitor cells isolated from a murine model of accelerated aging.
PG  - 1375-1382
LID - 10.1002/jor.23409 [doi]
AB  - Mice expressing reduced levels of ERCC1-XPF (Ercc1(-/Delta) mice) demonstrate 
      premature onset of age-related changes due to decreased repair of DNA damage. 
      Muscle-derived stem/progenitor cells (MDSPCs) isolated from Ercc1(-/Delta) mice have 
      an impaired capacity for cell differentiation. The mammalian target of rapamycin 
      (mTOR) is a critical regulator of cell growth in response to nutrient, hormone, 
      and oxygen levels. Inhibition of the mTOR pathway extends the lifespan of several 
      species. Here, we examined the role of mTOR in regulating the MDSPC dysfunction 
      that occurs with accelerated aging. We show that mTOR signaling pathways are 
      activated in Ercc1(-/Delta) MDSPCs compared with wild-type (WT) MDSPCs. Additionally, 
      inhibiting mTOR with rapamycin promoted autophagy and improved the myogenic 
      differentiation capacity of the Ercc1(-/Delta) MDSPCs. The percent of apoptotic and 
      senescent cells in Ercc1(-/Delta) MDSPC cultures was decreased upon mTOR inhibition. 
      These results establish that mTOR signaling contributes to stem cell dysfunction 
      and cell fate decisions in response to endogenous DNA damage. Therefore, mTOR 
      represents a potential therapeutic target for improving defective, aged stem 
      cells. (c) 2016 The Authors. Journal of Orthopaedic Research Published by Wiley 
      Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 
      35:1375-1382, 2017.
CI  - (c) 2016 The Authors. Journal of Orthopaedic Research Published by Wiley 
      Periodicals, Inc. on behalf of Orthopaedic Research Society.
FAU - Takayama, Koji
AU  - Takayama K
AD  - Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, 
      Pennsylvania.
AD  - Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, 
      Pennsylvania.
AD  - Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 
      Kobe 650-0017, Japan.
FAU - Kawakami, Yohei
AU  - Kawakami Y
AD  - Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, 
      Pennsylvania.
AD  - Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, 
      Pennsylvania.
AD  - Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 
      Kobe 650-0017, Japan.
FAU - Lavasani, Mitra
AU  - Lavasani M
AD  - Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, 
      Pennsylvania.
AD  - Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, 
      Pennsylvania.
FAU - Mu, Xiaodong
AU  - Mu X
AD  - Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, 
      Pennsylvania.
AD  - Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, 
      Pennsylvania.
AD  - Department of Orthopaedic Surgery, McGovern Medical School, University of Texas 
      Health Science Center at Houston, South Campus Research Building #3, 1881 East Rd 
      (3SCR) 6th Floor; Room 3708, Houston 77054, Texas.
AD  - Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, 
      Vail 81657, Colorado.
FAU - Cummins, James H
AU  - Cummins JH
AD  - Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, 
      Pennsylvania.
AD  - Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, 
      Pennsylvania.
AD  - Department of Orthopaedic Surgery, McGovern Medical School, University of Texas 
      Health Science Center at Houston, South Campus Research Building #3, 1881 East Rd 
      (3SCR) 6th Floor; Room 3708, Houston 77054, Texas.
FAU - Yurube, Takashi
AU  - Yurube T
AD  - Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, 
      Pennsylvania.
FAU - Kuroda, Ryosuke
AU  - Kuroda R
AD  - Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 
      Kobe 650-0017, Japan.
FAU - Kurosaka, Masahiro
AU  - Kurosaka M
AD  - Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 
      Kobe 650-0017, Japan.
FAU - Fu, Freddie H
AU  - Fu FH
AD  - Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, 
      Pennsylvania.
FAU - Robbins, Paul D
AU  - Robbins PD
AD  - Department of Metabolism and Aging, The Scripps Research Institute Florida, 
      Jupiter 33458, Florida.
FAU - Niedernhofer, Laura J
AU  - Niedernhofer LJ
AD  - Department of Metabolism and Aging, The Scripps Research Institute Florida, 
      Jupiter 33458, Florida.
FAU - Huard, Johnny
AU  - Huard J
AD  - Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, 
      Pennsylvania.
AD  - Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, 
      Pennsylvania.
AD  - Department of Orthopaedic Surgery, McGovern Medical School, University of Texas 
      Health Science Center at Houston, South Campus Research Building #3, 1881 East Rd 
      (3SCR) 6th Floor; Room 3708, Houston 77054, Texas.
AD  - Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, 
      Vail 81657, Colorado.
LA  - eng
GR  - P01 AG043376/AG/NIA NIH HHS/United States
GR  - R21 AG033907/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20160922
PL  - United States
TA  - J Orthop Res
JT  - Journal of orthopaedic research : official publication of the Orthopaedic 
      Research Society
JID - 8404726
RN  - 0 (DNA-Binding Proteins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.- (Endonucleases)
RN  - EC 3.1.- (Ercc1 protein, mouse)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Aging/*physiology
MH  - Animals
MH  - Apoptosis
MH  - Autophagy
MH  - Cell Differentiation
MH  - DNA-Binding Proteins/genetics
MH  - Disease Models, Animal
MH  - Endonucleases/genetics
MH  - Mice
MH  - Multipotent Stem Cells/*physiology
MH  - Muscle Development
MH  - Progeria/genetics/metabolism/*physiopathology
MH  - Signal Transduction
MH  - Sirolimus
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
PMC - PMC5516198
OTO - NOTNLM
OT  - ERCC1-XPF
OT  - aging
OT  - biology
OT  - mTOR
OT  - muscle
OT  - progeria
OT  - senescence
OT  - stem cells
EDAT- 2016/10/25 06:00
MHDA- 2017/09/28 06:00
PMCR- 2017/07/19
CRDT- 2016/08/31 06:00
PHST- 2015/12/04 00:00 [received]
PHST- 2016/08/26 00:00 [accepted]
PHST- 2016/10/25 06:00 [pubmed]
PHST- 2017/09/28 06:00 [medline]
PHST- 2016/08/31 06:00 [entrez]
PHST- 2017/07/19 00:00 [pmc-release]
AID - JOR23409 [pii]
AID - 10.1002/jor.23409 [doi]
PST - ppublish
SO  - J Orthop Res. 2017 Jul;35(7):1375-1382. doi: 10.1002/jor.23409. Epub 2016 Sep 22.