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.
Bibliographical noteFunding Information:
This project was funded in part by two NIH grants: R21 AG033907 (JH) and PO1 AG043376 (PR, JH, LN) and the Henry J. Mankin Endowed Chair at the University of Pittsburgh. The authors are grateful for the technical and scientific advice provided by Jessica Tebbets and Haizi Cheng, and the editorial assistance of Lavanya Rajagopalan, Bria King, and Ryan Warth.
- stem cells