title: mTOR signaling plays a critical role in the defects observed in muscle-derived stem/progenitor cells isolated from a murine model of accelerated aging.
abstract: Mice expressing reduced levels of ERCC1-XPF (Ercc1-/Δmice) demonstrate premature onset of age-related changes due to decreased repair of DNA damage. Muscle-derived stem/progenitor cells (MDSPCs) isolated from Ercc1-/Δmice 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-/ΔMDSPCs compared with wild-type (WT) MDSPCs. Additionally, inhibiting mTOR with rapamycin promoted autophagy and improved the myogenic differentiation capacity of the Ercc1-/ΔMDSPCs. The percent of apoptotic and senescent cells in Ercc1-/ΔMDSPC 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. © 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.
authors: Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.|Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, Pennsylvania.|Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors: Koji
authors: K
authors: Takayama
authors: Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.|Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, Pennsylvania.|Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors: Yohei
authors: Y
authors: Kawakami
authors: Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.|Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, Pennsylvania.
authors: Mitra
authors: M
authors: Lavasani
authors: Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.|Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, Pennsylvania.|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.|Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail 81657, Colorado.
authors: Xiaodong
authors: X
authors: Mu
authors: Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.|Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, Pennsylvania.|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.
authors: James H
authors: JH
authors: Cummins
authors: Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.
authors: Takashi
authors: T
authors: Yurube
authors: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors: Ryosuke
authors: R
authors: Kuroda
authors: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors: Masahiro
authors: M
authors: Kurosaka
authors: Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.
authors: Freddie H
authors: FH
authors: Fu
authors: Department of Metabolism and Aging, The Scripps Research Institute Florida, Jupiter 33458, Florida.
authors: Paul D
authors: PD
authors: Robbins
authors: Department of Metabolism and Aging, The Scripps Research Institute Florida, Jupiter 33458, Florida.
authors: Laura J
authors: LJ
authors: Niedernhofer
authors: Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.|Stem Cell Research Center, University of Pittsburgh, Pittsburgh 15219, Pennsylvania.|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.|Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail 81657, Colorado.
authors: Johnny
authors: J
authors: Huard
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D004720:Endonucleases / Q000235:genetics; D051379:Mice; D039902:Multipotent Stem Cells / Q000502:physiology*; D024510:Muscle Development; D011371:Progeria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D020123:Sirolimus
keywords: ERCC1-XPF; aging; biology; mTOR; muscle; progeria; senescence; stem cells