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(-/Δ) mice) demonstrate premature age-related changes due to their reduced capability to repair DNA damage. Muscle-derived stem/progenitor cells (MDSPCs) isolated from Ercc1(-/Δ) mice demonstrated an impaired capacity for cell differentiation. The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth in response to the availability of nutrients, hormones and oxygen levels. Inhibition of the mTOR pathway has been shown to extend the lifespans of several different species. In the current study, we examined the role of mTOR in the progressive dysfunction of MDSPCs in a mouse model of accelerated aging. We found that the mTOR signaling pathways are activated to a greater degree in Ercc1(-/Δ) MDSPCs when compared to those of wild-type (WT) MDSPCs. Additionally, inhibition of mTOR via treatment with rapamycin promoted autophagy and improved the myogenic differentiation capacity of Ercc1(-/Δ) MDSPCs. The ratios of apoptotic and senescent MDSPCs in Ercc1(-/Δ) mice were also reduced after treatment with rapamycin. In the setting of defective DNA repair mechanisms, these results suggest that mTOR signaling pathways contribute to progressive dysfunction, autophagy, apoptosis, and senescence of Ercc1(-/Δ) MDSPCs. Therefore, modification of mTOR signaling may represent an important approach to decelerate the aging process and to reduce the proportion of dysfunctional MDSPCs within target tissues. This article is protected by copyright. All rights reserved.