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

Stem Cell Reports
James P WhiteWilliam E Kraus

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.

Citations

Jan 29, 2020·Journal of Cachexia, Sarcopenia and Muscle·Shuang RongWei Yang
Mar 12, 2020·International Journal of Molecular Sciences·Hiroyuki YamakawaShinsuke Yuasa
Sep 17, 2020·Biomolecules·Gian Luigi RussoAdriana Borriello
Aug 23, 2020·Nutrients·Thanusha GanesanMohammed Abdullah Alshawsh
Mar 3, 2020·Frontiers in Physiology·Emily E HowardNancy R Rodriguez
Jul 23, 2020·Nature Metabolism·Gurpreet S BahtJames P White
Jan 11, 2020·Frontiers in Cell and Developmental Biology·Gunjan Purohit, Jyotsna Dhawan
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Nov 10, 2020·Frontiers in Cell and Developmental Biology·Yutaka KobayashiHiroyuki Inose
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Methods Mentioned

BETA
fluorescence-activated cell sorting
FACS
Assay
dissection

Software Mentioned

FIJI
Cellomics ArrayScan
GraphPad Prism
ImageJ

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