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Stem Cell Reports. 2018 Aug 14;11(2):425-439. doi: 10.1016/j.stemcr.2018.06.014. Epub 2018 Jul 19.

The AMPK/p27Kip1 Axis Regulates Autophagy/Apoptosis Decisions in Aged Skeletal Muscle Stem Cells.

Author information

1
Division of Hematology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA; Duke Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27701, USA. Electronic address: james.white@duke.edu.
2
Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, PA 19406, USA.
3
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA.
4
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA; Duke Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27701, USA; Division of Rheumatology, Duke University School of Medicine, Durham, NC 27701, USA.
5
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA; Duke Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27701, USA; Division of Cardiology, Duke University School of Medicine, Durham, NC 27701, USA.

Abstract

Skeletal muscle stem cell (MuSC) function declines with age and contributes to impaired muscle regeneration in older individuals. Acting through AMPK/p27Kip1, we have identified a pathway regulating the balance between autophagy, apoptosis, and senescence in aged MuSCs. While p27Kip1 is implicated in MuSC aging, its precise role and molecular mechanism have not been elucidated. Age-related MuSC dysfunction was associated with reduced autophagy, increased apoptosis, and hypophosphorylation of AMPK and its downstream target p27Kip1. AMPK activation or ectopic expression of a phosphomimetic p27Kip1 mutant was sufficient to suppress in vitro apoptosis, increase proliferation, and improve in vivo transplantation efficiency of aged MuSCs. Moreover, activation of the AMPK/p27Kip1 pathway reduced markers of cell senescence in aged cells, which was, in part, dependent on p27Kip1 phosphorylation. Thus, the AMPK/p27Kip1 pathway likely regulates the autophagy/apoptosis balance in aged MuSCs and may be a potential target for improving muscle regeneration in older individuals.

KEYWORDS:

AMPK; aging; apoptosis; autophagy; caloric restriction; cell transplantation; muscle stem cell; p27Kip1; regeneration; senescence

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