Abstract
Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF-β)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular understanding, combined with data that human satellite cells remain intrinsically young, introduced novel therapeutic targets. Indeed, activation of MAPK/Notch restored ‘youthful’ myogenic responses to satellite cells from 70-year-old humans, rendering them similar to cells from 20-year-old humans. These findings strongly suggest that aging of human muscle maintenance and repair can be reversed by ‘youthful’ calibration of specific molecular pathways.
Highlights
The rate of metabolism and cumulative oxidative damage to DNA and proteins, as well as genomic instability and mutations to mitochondrial DNA, have all been implicated in determining the intrinsic rate of cell aging and species’ life-span (Cevenini et al, 2008; Vijg & Campisi, 2008)
We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF-b)/phospho Smad3
Exploring the evolutionary and developmental conservation of Notch and mitogen-activated protein kinase (MAPK) cross-talk, we examined whether (1) MAPK pathway strength becomes diminished in old human muscles, as compared to youngs and (2) whether MAPK signalling intensity is causal for Notch activation and myogenic properties of human satellite cells
Summary
The rate of metabolism and cumulative oxidative damage to DNA and proteins, as well as genomic instability and mutations to mitochondrial DNA, have all been implicated in determining the intrinsic rate of cell aging and species’ life-span (Cevenini et al, 2008; Vijg & Campisi, 2008). (2) Institute of Sports Medicine and Centre of Healthy Aging, Faculty of Health Science, University of Copenhagen, Denmark. Our work in the mouse model defined that injury to myofibres, induces expression of the Notch ligand Delta, which thereby acts as a positional cue to activate Notch in satellite cells and causes them to break quiescence and to proliferate (Conboy & Rando, 2002; Conboy et al, 2003). Notch activation becomes lacking due to diminished Delta expression in myofibres and in satellite cells. Such decline in Notch activation is further compounded by excessive TGF-b/phospho-Smad (pSmad), causing an accumulation of cyclin-dependant kinase (CDK) inhibitors in muscle stem cells and preventing their regenerative responses (Carlson et al, 2008a; Conboy et al, 2003)
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