Title: Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging

Author: Daniel I. Benjamin, Jamie O. Brett, Pieter Both, Joel S. Benjamin, Heather L. Ishak, Jengmin Kang, Soochi Kim, Mingyu Chung, Marina Arjona, Christopher W. Nutter, Jenna H. Tan, Ananya K. Krishnan, Hunter Dulay, Sharon M. Louie, Antoine de Morree, Daniel K. Nomura, Thomas A. Rando

Issue&Volume: 2023-02-27

Abstract: With age, skeletal muscle stem cells (MuSCs) activate out of quiescence more slowlyand with increased death, leading to defective muscle repair. To explore the molecularunderpinnings of these defects, we combined multiomics, single-cell measurements,and functional testing of MuSCs from young and old mice. The multiomics approach allowedus to assess which changes are causal, which are compensatory, and which are simplycorrelative. We identified glutathione (GSH) metabolism as perturbed in old MuSCs,with both causal and compensatory components. Contrary to young MuSCs, old MuSCs exhibita population dichotomy composed of GSHhigh cells (comparable with young MuSCs) and GSHlow cells with impaired functionality. Mechanistically, we show that antagonism betweenNRF2 and NF-κB maintains this bimodality. Experimental manipulation of GSH levelsaltered the functional dichotomy of aged MuSCs. These findings identify a novel mechanismof stem cell aging and highlight glutathione metabolism as an accessible target forreversing MuSC aging.

DOI: 10.1016/j.cmet.2023.02.001

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00037-2

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