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

J Orthop Res. 2017 Jul;35(7):1375-1382. doi: 10.1002/jor.23409. Epub 2016 Sep 22.


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. © 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.

Keywords: ERCC1-XPF; aging; biology; mTOR; muscle; progeria; senescence; stem cells.

MeSH terms

  • Aging / physiology*
  • Animals
  • Apoptosis
  • Autophagy
  • Cell Differentiation
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Endonucleases / genetics
  • Mice
  • Multipotent Stem Cells / physiology*
  • Muscle Development
  • Progeria / genetics
  • Progeria / metabolism
  • Progeria / physiopathology*
  • Signal Transduction
  • Sirolimus
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*


  • DNA-Binding Proteins
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Endonucleases
  • Ercc1 protein, mouse
  • Sirolimus