Sestrins regulate muscle stem cell metabolic homeostasis

Benjamin A Yang; Jesus Castor-Macias; Paula Fraczek; Ashley Cornett; Lemuel A Brown; Myungjin Kim; Susan V Brooks; Isabelle M A Lombaert; Jun Hee Lee; Carlos A Aguilar

doi:10.1016/j.stemcr.2021.07.014

Sestrins regulate muscle stem cell metabolic homeostasis

Stem Cell Reports. 2021 Sep 14;16(9):2078-2088. doi: 10.1016/j.stemcr.2021.07.014. Epub 2021 Aug 12.

Authors

Affiliations

¹ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
² Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: caguilar@umich.edu.

Abstract

The health and homeostasis of skeletal muscle are preserved by a population of tissue-resident muscle stem cells (MuSCs) that maintain a state of mitotic and metabolic quiescence in adult tissues. The capacity of MuSCs to preserve the quiescent state declines with aging and metabolic insults, promoting premature activation and stem cell exhaustion. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. We show that SESTRIN1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle, and shifts in metabolic flux. Aged SESTRIN1,2 knockout mice exhibited loss of MuSCs and a reduced ability to regenerate injured muscle. These findings demonstrate that Sestrins help maintain metabolic pathways in MuSCs that protect quiescence against aging.

Keywords: RNA sequencing; aging; mTORC1; metabolism; oxidative stress; reactive oxygen species; regeneration; satellite cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Age Factors
Animals
Biomarkers
Cell Culture Techniques
Cell Separation / methods
Energy Metabolism*
Gene Expression Profiling
Gene Expression Regulation
Gene Knockdown Techniques
High-Throughput Nucleotide Sequencing
Homeostasis*
Immunohistochemistry
Immunophenotyping
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Mice, Knockout
Muscle, Skeletal / cytology*
Regeneration
Satellite Cells, Skeletal Muscle / cytology
Satellite Cells, Skeletal Muscle / metabolism
Sestrins / deficiency
Sestrins / genetics*
Sestrins / metabolism
Stem Cells / cytology
Stem Cells / metabolism*

Substances

Biomarkers
Sestrins
Mechanistic Target of Rapamycin Complex 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding