mTOR signaling plays a critical role in the defects observed in muscle-derived stem/progenitor cells isolated from a murine model of accelerated aging

Koji Takayama, Yohei Kawakami, Mitra Lavasani, Xiaodong Mu, James H. Cummins, Takashi Yurube, Ryosuke Kuroda, Masahiro Kurosaka, Freddie H. Fu, Paul D. Robbins, Laura J. Niedernhofer, Johnny Huard

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Mice expressing reduced levels of ERCC1-XPF (Ercc1−/Δ mice) demonstrate premature onset of age-related changes due to decreased repair of DNA damage. Muscle-derived stem/progenitor cells (MDSPCs) isolated from Ercc1−/Δ 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−/Δ MDSPCs compared with wild-type (WT) MDSPCs. Additionally, inhibiting mTOR with rapamycin promoted autophagy and improved the myogenic differentiation capacity of the Ercc1−/Δ MDSPCs. The percent of apoptotic and senescent cells in Ercc1−/Δ 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.

Original languageEnglish (US)
Pages (from-to)1375-1382
Number of pages8
JournalJournal of Orthopaedic Research
Volume35
Issue number7
DOIs
StatePublished - Jul 2017

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Sirolimus
Stem Cells
Muscles
DNA Damage
Autophagy
Age of Onset
Cell Differentiation
Cell Culture Techniques

Keywords

  • ERCC1-XPF
  • aging
  • biology
  • mTOR
  • muscle
  • progeria
  • senescence
  • stem cells

Cite this

mTOR signaling plays a critical role in the defects observed in muscle-derived stem/progenitor cells isolated from a murine model of accelerated aging. / Takayama, Koji; Kawakami, Yohei; Lavasani, Mitra; Mu, Xiaodong; Cummins, James H.; Yurube, Takashi; Kuroda, Ryosuke; Kurosaka, Masahiro; Fu, Freddie H.; Robbins, Paul D.; Niedernhofer, Laura J.; Huard, Johnny.

In: Journal of Orthopaedic Research, Vol. 35, No. 7, 07.2017, p. 1375-1382.

Research output: Contribution to journalArticle

Takayama, Koji ; Kawakami, Yohei ; Lavasani, Mitra ; Mu, Xiaodong ; Cummins, James H. ; Yurube, Takashi ; Kuroda, Ryosuke ; Kurosaka, Masahiro ; Fu, Freddie H. ; Robbins, Paul D. ; Niedernhofer, Laura J. ; Huard, Johnny. / mTOR signaling plays a critical role in the defects observed in muscle-derived stem/progenitor cells isolated from a murine model of accelerated aging. In: Journal of Orthopaedic Research. 2017 ; Vol. 35, No. 7. pp. 1375-1382.
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