Journal
STEM CELL REPORTS
Volume 16, Issue 9, Pages 2078-2088Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2021.07.014
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Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [P30 AR069620]
- 3M Foundation
- American Federation for Aging Research Grant for Junior Faculty
- Department of Defense and Congressionally Directed Medical Research Program [W81XWH2010336]
- University of Michigan Geriatrics Center
- National Institute on Aging [P01 AG051442, P30 AG024824]
- National Institute of Biomedical Imaging and Bioengineering Training Award [T32 EB005582]
- U.S. Department of Defense (DOD) [W81XWH2010336] Funding Source: U.S. Department of Defense (DOD)
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The maintenance of metabolic pathways in MuSCs is crucial for the preservation of quiescence, with Sestrins playing a key role in this function. Loss of Sestrins during aging can lead to loss of MuSCs and reduced muscle regeneration capacity.
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.
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