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AMPK Inhibits mTOR-Driven Keratinocyte Proliferation after Skin Damage and Stress

Elizabeth D Crane1, Wesley Wong1, Hui Zhang1

  • 1Department of Biology, Northeastern University, Boston, Massachusetts, USA.

The Journal of Investigative Dermatology
|March 20, 2021
PubMed

Insights

AMPK in skin cells (KCs) controls proliferation after injury. Loss of AMPK leads to excessive KC growth, which can be blocked by mTORC1 inhibitors like rapamycin.

Area of Science:

  • Dermatology
  • Molecular Biology
  • Metabolism

Background:

  • Epidermal keratinocytes (KCs) must proliferate for skin repair, but the mechanisms controlling this growth after stress are unclear.
  • AMP-activated protein kinase (AMPK), a key energy metabolism regulator, has known links to skin stress and cancer, but its role in KC proliferation is not fully understood.

Purpose of the Study:

  • To investigate the role of epidermal AMPK in regulating keratinocyte proliferation during physiological skin repair.
  • To determine if AMPK restrains keratinocyte growth after various forms of epidermal stress.

Main Methods:

  • Genetic deletion of AMPK in adult mouse keratin 14-expressing keratinocytes.
  • Assessment of keratinocyte proliferation and mTOR signaling pathways following acute wounding, UVB exposure, and phorbol ester application.
  • Treatment with the mTORC1 inhibitor rapamycin and the diabetes drug metformin.

Main Results:

  • Loss of epidermal AMPK led to keratinocyte hyperproliferation and hyperactive mTOR signaling in response to wounding, UVB, and phorbol ester.
  • The excessive proliferation caused by AMPK loss was completely inhibited by rapamycin.
  • The diabetes drug metformin suppressed stress-induced keratinocyte proliferation, dependent on AMPK activity.

Conclusions:

  • Epidermal AMPK acts as a crucial brake on keratinocyte proliferation after tissue injury.
  • AMPK restrains the mTORC1 pathway to control epidermal growth and maintain tissue homeostasis.
  • These findings highlight AMPK as a potential therapeutic target for skin repair and diseases involving aberrant keratinocyte proliferation.

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