Molecular aging and rejuvenation of human muscle stem cells

Department of Bioengineering, University of California, Berkeley, Berkeley CA, USA.
EMBO Molecular Medicine (Impact Factor: 8.67). 11/2009; 1(8-9):381-91. DOI: 10.1002/emmm.200900045
Source: PubMed


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-beta)/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.

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    • " estimation of fiber type specific satellite cell content in healthy young men . Whether the same number of muscle fibers is enough to make a reliable estimation of satellite cell content in other populations remains to be established , especially as satellite cell content has been suggested to decrease with advancing age ( Verney et al . , 2008 ; Carlson et al . , 2009 ; Verdijk et al . , 2009 , 2010 , 2012 , 2014 ; McKay et al . , 2012 , 2013 ; Leenders et al . , 2013 ; Suetta et al . , 2013 ; Mackey et al . , 2014 ; Snijders et al . , 2014c ) . Counting all satellite cells in a muscle section ( thereby increasing the number of fibers included in the analyses ) is preferred as this will prevent subjec"
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    • "In agreement, it has been postulated that satellite cell number does not reflect a change in the regenerative ability of the muscle. In addition to the reports stating no decrease in satellite cell number with age, others indicate an increase in the number of resident satellite cells in aged skeletal muscle (Beccafico et al., 2007; Brooks et al., 2009; Carlson et al., 2009; Conboy et al., 2003; Conboy and Rando, 2005; Day et al., 2010; Dreyer et al., 2006; Nnodim, 2000; Shefer et al., 2006). As mentioned above, in accordance with this last suggestion, evidence from in vitro assays shows that aged cultures of murine myoblasts are resistant to death by apoptosis, probably due to the loss of mitochondrial DNA (mtDNA) by high passage numbers (Pronsato et al., 2013). "
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    • "Declines in the activation of myogenic molecular pathways, including phosphatidylinositol 3-kinase (PI3K/Akt) signaling pathway, which directs cellular apoptosis, as well as Notch signaling, indispensable for MuSC proliferation immediately following injury (Conboy et al., 2003), have been implicated as culprits in age-related MuSC dysfunction. The mitogen activated protein kinase (MAPK) pathway, a positive regulator of Notch, is similarly age-responsive (Carlson et al., 2009a). Finally, it appears that decreased signaling for myogenesis is concomitant with increased activation of fibrogenic pathways owing to an age-related increased activation of the canonical Wnt signaling pathway, which contributes to a myogenic-to-fibrogenic conversion of MuSCs (Brack et al., 2007). "
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