AMPK Restrains Epidermal Stem Cell Aging by Inhibiting mTORC1-Induced Hyper-Proliferation

Abstract

Epidermal stem cells (ESCs) rapidly proliferate to repair the skin barrier and a strict control of division is necessary to sustain stem cell growth capacity. AMP-activated protein kinase (AMPK) is an important signaling mediator of energy metabolism previously associated with skin stress and cancer, yet its impact on ESC proliferation is not known. To examine the requirement of ESC AMPK in physiologic skin repair, we deleted both AMPKα subunits within adult, Keratin 14-expressing ESCs. AMPKα deletion resulted in extensive hyperproliferation following acute wounding, UVB exposure, and phorbol ester application. This augmented stress-induced proliferation was driven by hyperactive mTOR signaling and could be completely blocked by the mTORC1 inhibitor rapamycin. Unexpectedly, after repetitive proliferative stress, ESC AMPKα loss resulted in fewer tumors due to premature growth arrest and reduced ESC proliferative capacity akin to accelerated aging. These findings show that AMPK is essential for controlling mTORC1-driven ESC proliferation and biological aging.

Keywords: AMPK, mTOR, proliferation, epidermal stem cell, epithelia, skin, aging, senescence