PGC-1s shape epidermal physiology by modulating keratinocyte proliferation and terminal differentiation

Simon-Pierre Gravel; Youcef Ben Khalifa; Shawn McGuirk; Catherine St-Louis; Karl M Laurin; Émilie Lavallée; Damien Benas; Stéphanie Desbouis; Frédéric Amaral; Damien D'Amours; Lionel Breton; Sibylle Jäger; Julie St-Pierre

doi:10.1016/j.isci.2023.106314

PGC-1s shape epidermal physiology by modulating keratinocyte proliferation and terminal differentiation

iScience. 2023 Mar 2;26(4):106314. doi: 10.1016/j.isci.2023.106314. eCollection 2023 Apr 21.

Authors

Simon-Pierre Gravel^{1

2

3}, Youcef Ben Khalifa⁴, Shawn McGuirk^{1

2}, Catherine St-Louis^{5

6}, Karl M Laurin³, Émilie Lavallée³, Damien Benas⁷, Stéphanie Desbouis⁴, Frédéric Amaral⁴, Damien D'Amours^{8

5}, Lionel Breton⁴, Sibylle Jäger⁴, Julie St-Pierre^{1

2

5

6}

Affiliations

¹ Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
² Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada.
³ Faculté de Pharmacie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁴ L'Oréal Research & Innovation, 93600 Aulnay-sous-Bois, France.
⁵ Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
⁶ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
⁷ EPISKIN, 69366 Lyon Cedex 7, France.
⁸ Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.

Abstract

Skin plays central roles in systemic physiology, and it undergoes significant functional changes during aging. Members of the peroxisome proliferator-activated receptor-gamma coactivator (PGC-1) family (PGC-1s) are key regulators of the biology of numerous tissues, yet we know very little about their impact on skin functions. Global gene expression profiling and gene silencing in keratinocytes uncovered that PGC-1s control the expression of metabolic genes as well as that of terminal differentiation programs. Glutamine emerged as a key substrate promoting mitochondrial respiration, keratinocyte proliferation, and the expression of PGC-1s and terminal differentiation programs. Importantly, gene silencing of PGC-1s reduced the thickness of a reconstructed living human epidermal equivalent. Exposure of keratinocytes to a salicylic acid derivative potentiated the expression of PGC-1s and terminal differentiation genes and increased mitochondrial respiration. Overall, our results show that the PGC-1s are essential effectors of epidermal physiology, revealing an axis that could be targeted in skin conditions and aging.

Keywords: dermatology; human metabolism; molecular mechanism of gene regulation; physiology.