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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    ABSTRACT: Skeletal muscle satellite cells are considered to play a crucial role in muscle fiber maintenance, repair and remodeling. Our knowledge of the role of satellite cells in muscle fiber adaptation has traditionally relied on in vitro cell and in vivo animal models. Over the past decade, a genuine effort has been made to translate these results to humans under physiological conditions. Findings from in vivo human studies suggest that satellite cells play a key role in skeletal muscle fiber repair/remodeling in response to exercise. Mounting evidence indicates that aging has a profound impact on the regulation of satellite cells in human skeletal muscle. Yet, the precise role of satellite cells in the development of muscle fiber atrophy with age remains unresolved. This review seeks to integrate recent results from in vivo human studies on satellite cell function in muscle fiber repair/remodeling in the wider context of satellite cell biology whose literature is largely based on animal and cell models.
    Frontiers in Physiology 11/2015; 6. DOI:10.3389/fphys.2015.00283 · 3.53 Impact Factor
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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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    ABSTRACT: The loss of muscle mass and strength with aging, referred to as sarcopenia, is a prevalent condition among the elderly. Although the molecular mechanisms underlying sarcopenia are unclear, evidence suggests that an age-related acceleration of myocyte loss via apoptosis might be responsible for muscle perfomance decline. Interestingly, sarcopenia has been associated to a deficit of sex hormones which decrease upon aging. The skeletal muscle ability to repair and regenerate itself would not be possible without satellite cells, a subpopulation of cells that remain quiescent throughout life. They are activated in response to stress, enabling them to guide skeletal muscle regeneration. Thus, these cells could be a key factor to overcome sarcopenia. Of importance, satellite cells are 17β-estradiol (E2) and Testosterone (T) targets. In this review, we summarize potential mechanisms through which these hormones regulate satellite cells activation during skeletal muscle regeneration in the elderly. The advance in its understanding will help to the development of potential therapeutic agents to alleviate and treat sarcopenia and other related myophaties. Copyright © 2015. Published by Elsevier B.V.
    Ageing research reviews 08/2015; DOI:10.1016/j.arr.2015.07.011 · 4.94 Impact Factor
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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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    ABSTRACT: Klotho is a powerful longevity protein that has been linked to the prevention of muscle atrophy, osteopenia, and cardiovascular disease. Similar anti-aging effects have also been ascribed to exercise and physical activity. While an association between muscle function and Klotho expression has been previously suggested from longitudinal cohort studies, a direct relationship between circulating Klotho and skeletal muscle has not been investigated. In this paper, we present a review of the literature and preliminary evidence that, together, suggests Klotho expression may be modulated by skeletal muscle activity. Our pilot clinical findings performed in young and aged individuals suggest that circulating Klotho levels are upregulated in response to an acute exercise bout, but that the response may be dependent on fitness level. A similar upregulation of circulating Klotho is also observed in response to an acute exercise in young and old mice, suggesting that this may be a good model for mechanistically probing the role of physical activity on Klotho expression. Finally, we highlight overlapping signaling pathways that are modulated by both Klotho and skeletal muscle and propose potential mechanisms for cross-talk between the two. It is hoped that this review will stimulate further consideration of the relationship between skeletal muscle activity and Klotho expression, potentially leading to important insights into the well-documented systemic anti-aging effects of exercise.
    Frontiers in Physiology 06/2014; 5:189. DOI:10.3389/fphys.2014.00189 · 3.53 Impact Factor
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