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Regulation of Muscle Satellite Cell Function in Tissue Homeostasis and Aging

2015; Elsevier BV; Volume: 16; Issue: 6 Linguagem: Inglês

10.1016/j.stem.2015.05.007

1934-5909

Alessandra Sacco, Prem Puri,

Spaceflight effects on biology

Age-related muscle decline is associated with functional impairment of satellite cells (SCs). Conflicting data suggest dysregulation of cell-extrinsic or -intrinsic factors can independently contribute to such impairment. Here, we emphasize the importance of identifying nodes that integrate these factors into feed-forward circuits, which could provide targets for therapeutic intervention. Age-related muscle decline is associated with functional impairment of satellite cells (SCs). Conflicting data suggest dysregulation of cell-extrinsic or -intrinsic factors can independently contribute to such impairment. Here, we emphasize the importance of identifying nodes that integrate these factors into feed-forward circuits, which could provide targets for therapeutic intervention. Satellite cells (SCs) are tissue-resident muscle stem cells required for postnatal tissue growth and repair through replacement of compromised myofibers. Recent studies have revealed that progressive impairment of SC function correlates with the decline of muscle regenerative potential typically observed during mammalian aging. This functional exhaustion of regenerative potential has been proposed to arise from loss of integrity of the regulatory networks that maintain a quiescent pool of reserve SCs and ensure proper transitions between SC quiescence, activation, and transition into committed progenitors. Quiescent SCs are poised to rapidly respond to microenvironmental cues, such as those provided by extracellular and cellular components of the SC niche, and SC activation occurs as a tightly regulated event in response to muscle injury. The coordinated temporospatial interplay between SCs, differentiated myofibers, and interstitial cellular components of the SC niche is therefore essential for maintaining SC number and function throughout life. Progressive dysregulation of this interplay during aging is emerging as a major cause of loss of SC quiescence. Experiments utilizing parabiotic conjoining of mice showed that exposure of aged SCs to a youthful environment is sufficient to restore their regenerative potential, indicating a critical role of systemic components in regulating SC function (Brack et al., 2007Brack A.S. Conboy M.J. Roy S. Lee M. Kuo C.J. Keller C. Rando T.A. Science. 2007; 317: 807-810Crossref PubMed Scopus (1108) Google Scholar, Conboy et al., 2005Conboy I.M. Conboy M.J. Wagers A.J. Girma E.R. Weissman I.L. Rando T.A. Nature. 2005; 433: 760-764Crossref PubMed Scopus (1657) Google Scholar). These experiments revealed a previously unappreciated reversibility of age-associated impairment of SCs by restoring the physiological network of extrinsic cues present in young organisms. More recently, work has identified aberrant activation of several signaling pathways, such as STAT3, p38, FGF2, and canonical Wnt signaling, and a reduction of Notch pathway activity in aged muscles. Interestingly, all of these changes impacted on the transition of SCs to a progenitor stage, leading to impaired control of quiescence and self-renewal (Bernet et al., 2014Bernet J.D. Doles J.D. Hall J.K. Kelly Tanaka K. Carter T.A. Olwin B.B. Nat. Med. 2014; 20: 265-271Crossref PubMed Scopus (362) Google Scholar, Brack et al., 2007Brack A.S. Conboy M.J. Roy S. Lee M. Kuo C.J. Keller C. Rando T.A. Science. 2007; 317: 807-810Crossref PubMed Scopus (1108) Google Scholar, Chakkalakal et al., 2012Chakkalakal J.V. Jones K.M. Basson M.A. Brack A.S. Nature. 2012; 490: 355-360Crossref PubMed Scopus (548) Google Scholar, Cosgrove et al., 2014Cosgrove B.D. Gilbert P.M. Porpiglia E. Mourkioti F. Lee S.P. Corbel S.Y. Llewellyn M.E. Delp S.L. Blau H.M. Nat. Med. 2014; 20: 255-264Crossref PubMed Scopus (423) Google Scholar, Price et al., 2014Price F.D. von Maltzahn J. Bentzinger C.F. Dumont N.A. Yin H. Chang N.C. Wilson D.H. Frenette J. Rudnicki M.A. Nat. Med. 2014; 20: 1174-1181Crossref PubMed Scopus (258) Google Scholar, Tierney et al., 2014Tierney M.T. Aydogdu T. Sala D. Malecova B. Gatto S. Puri P.L. Latella L. Sacco A. Nat. Med. 2014; 20: 1182-1186Crossref PubMed Scopus (252) Google Scholar). Elegant studies from the Brack group provided clear evidence that during aging, increased FGF2 signaling in the aged niche can cause SCs to lose quiescence (Chakkalakal et al., 2012Chakkalakal J.V. Jones K.M. Basson M.A. Brack A.S. Nature. 2012; 490: 355-360Crossref PubMed Scopus (548) Google Scholar). Subsequent studies linked altered FGF2 signaling with constitutive, aberrant activation of the p38 MAPK pathway, leading to impaired self-renewal of aged SCs (Bernet et al., 2014Bernet J.D. Doles J.D. Hall J.K. Kelly Tanaka K. Carter T.A. Olwin B.B. Nat. Med. 2014; 20: 265-271Crossref PubMed Scopus (362) Google Scholar, Cosgrove et al., 2014Cosgrove B.D. Gilbert P.M. Porpiglia E. Mourkioti F. Lee S.P. Corbel S.Y. Llewellyn M.E. Delp S.L. Blau H.M. Nat. Med. 2014; 20: 255-264Crossref PubMed Scopus (423) Google Scholar). Intriguingly, these two studies performed transplantation assays of aged SCs into younger mice and showed that the aged SC phenotype could not be rescued by a young environment—a finding seemingly in conflict with the conclusions from parabiosis experiments (Brack et al., 2007Brack A.S. Conboy M.J. Roy S. Lee M. Kuo C.J. Keller C. Rando T.A. Science. 2007; 317: 807-810Crossref PubMed Scopus (1108) Google Scholar, Conboy et al., 2005Conboy I.M. Conboy M.J. Wagers A.J. Girma E.R. Weissman I.L. Rando T.A. Nature. 2005; 433: 760-764Crossref PubMed Scopus (1657) Google Scholar). While this discrepancy may be due to the different experimental settings and assays utilized, we argue that transplanted SCs might be "primed" by the aged organism of derivation and adopt a constitutive, refractory phenotype upon manipulations, such as isolation and transplantation, that are known to artificially activate SCs. Thus, the cell-autonomous resistance to youthful cues observed after transplantation of aged SCs could arise from changes that cannot be erased by exposure to a young environment. Such a priming mechanism could be mediated by epigenetic changes during aging and in response to extrinsic signals. Consistently, Liu et al. identified transcriptional and epigenetic signatures of SC aging, including loss of bivalency at promoters of developmental genes. Bivalent promoters are simultaneously marked by activatory and repressory marks (H3K4me3 and H3K27me3, respectively). Such promoters are associated with genes poised to be activated during lineage commitment in embryonic stem cells and correlate with stemness in quiescent SCs (Liu et al., 2013Liu L. Cheung T.H. Charville G.W. Hurgo B.M. Leavitt T. Shih J. Brunet A. Rando T.A. Cell Rep. 2013; 4: 189-204Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar). As such, it is possible that progressive loss of bivalent domains compromises quiescence in aging SCs, and such domains might be restored by exposure to youthful cues when SCs are in their native environment. In contrast, physical procedures, such as isolation and transplantation that notoriously lead to SC activation, might impose a resistance to external cues and render these epigenetic changes irreversible. While cell non-autonomous changes in the aged SC niche may provide the initial trigger ultimately leading to epigenetic dysregulation and compromised SC function, identification of nodes that integrate these disparate cell-intrinsic and -extrinsic signals to sustain the irreversibility of this process might reveal therapeutic targets for anti-aging interventions. The finding that pharmacological blockade of FGF2, p38, and STAT3 signaling, which are aberrantly activated in aged SCs, can reverse SC impairment (Bernet et al., 2014Bernet J.D. Doles J.D. Hall J.K. Kelly Tanaka K. Carter T.A. Olwin B.B. Nat. Med. 2014; 20: 265-271Crossref PubMed Scopus (362) Google Scholar, Brack et al., 2007Brack A.S. Conboy M.J. Roy S. Lee M. Kuo C.J. Keller C. Rando T.A. Science. 2007; 317: 807-810Crossref PubMed Scopus (1108) Google Scholar, Chakkalakal et al., 2012Chakkalakal J.V. Jones K.M. Basson M.A. Brack A.S. Nature. 2012; 490: 355-360Crossref PubMed Scopus (548) Google Scholar, Cosgrove et al., 2014Cosgrove B.D. Gilbert P.M. Porpiglia E. Mourkioti F. Lee S.P. Corbel S.Y. Llewellyn M.E. Delp S.L. Blau H.M. Nat. Med. 2014; 20: 255-264Crossref PubMed Scopus (423) Google Scholar, Price et al., 2014Price F.D. von Maltzahn J. Bentzinger C.F. Dumont N.A. Yin H. Chang N.C. Wilson D.H. Frenette J. Rudnicki M.A. Nat. Med. 2014; 20: 1174-1181Crossref PubMed Scopus (258) Google Scholar, Tierney et al., 2014Tierney M.T. Aydogdu T. Sala D. Malecova B. Gatto S. Puri P.L. Latella L. Sacco A. Nat. Med. 2014; 20: 1182-1186Crossref PubMed Scopus (252) Google Scholar) indicates that these pathways control downstream feed-forward circuits that establish and maintain aging-associated changes in SCs. Intriguingly, p38 and STAT3 signaling are essential activators of skeletal myogenesis and promote SC differentiation during regeneration (Price et al., 2014Price F.D. von Maltzahn J. Bentzinger C.F. Dumont N.A. Yin H. Chang N.C. Wilson D.H. Frenette J. Rudnicki M.A. Nat. Med. 2014; 20: 1174-1181Crossref PubMed Scopus (258) Google Scholar, Tierney et al., 2014Tierney M.T. Aydogdu T. Sala D. Malecova B. Gatto S. Puri P.L. Latella L. Sacco A. Nat. Med. 2014; 20: 1182-1186Crossref PubMed Scopus (252) Google Scholar), thereby raising the question of how activation of these same signaling pathways can impair SC performance in aged muscles. One possibility is altered cellular distribution of activated pathway components. Presumably, activated signaling components are restricted to committed progeny of SC in young muscles but become uniformly activated in all SCs of old mice. Moreover, changes in the epigenetic landscape in aged SCs might alter chromatin accessibility to downstream signaling pathway effectors, thereby modulating transcriptional output. The cellular basis underlying the switch from physiological activation of the p38 and STAT3 pathways in young SCs (i.e., by regeneration cues) to age-associated constitutive activation has not yet been conclusively demonstrated. One potential mechanism underlying this switch is the aberrant levels of inflammatory cytokines typically observed in aged organisms. Consistent with extrinsic changes (i.e., the cellular components of the niche, the related secretome, and biomechanical cues) activating a feed-forward mechanism that amplifies age-related events in SCs, exposure to biomaterials that mimic the biomechanical properties of young muscles can rescue the age-related defects of SCs (Cosgrove et al., 2014Cosgrove B.D. Gilbert P.M. Porpiglia E. Mourkioti F. Lee S.P. Corbel S.Y. Llewellyn M.E. Delp S.L. Blau H.M. Nat. Med. 2014; 20: 255-264Crossref PubMed Scopus (423) Google Scholar). A second possibility is that shifts in the heterogeneity of the SC population during aging underlie this switch in activation. Consistently, p38 inhibition and biomechanical cues may only target a subset of the aged SC compartment and change the cellular composition of the SC pool rather than act to reverse the aged phenotype per se. As mentioned above, cellular senescence is one process associated with the functional decline of aged tissues. While the precise relationship between cellular senescence and aging has not been determined, increasing evidence suggests that senescence can be a "point of no return" at which aging SCs acquire a cell-autonomous phenotype that limits their functional capacity. Of interest, a recent breakthrough from the Munoz-Canoves group has identified a number of senescence-associated features in SCs isolated from over 2-year-old (geriatric) mice. This phenomenon has been termed "geroconversion" and appears to be mediated by de-repression of the cell cycle inhibitor p16 (INK4a)—a hallmark of cellular senescence (Sousa-Victor et al., 2014Sousa-Victor P. Gutarra S. García-Prat L. Rodriguez-Ubreva J. Ortet L. Ruiz-Bonilla V. Jardí M. Ballestar E. González S. Serrano A.L. et al.Nature. 2014; 506: 316-321Crossref PubMed Scopus (624) Google Scholar). This evidence suggests that an altered nuclear landscape in SCs from aged animals might deregulate gene expression and even alter accessibility of chromatin to certain signaling pathways. In this regard, alterations of histone modifications (i.e., the reduction of genes marked by a "bivalent" chromatin) and histone variants detected in aged SCs (Liu et al., 2013Liu L. Cheung T.H. Charville G.W. Hurgo B.M. Leavitt T. Shih J. Brunet A. Rando T.A. Cell Rep. 2013; 4: 189-204Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar) might alter the physiological response to environmental signals. Thus, in addition to an elevated concentration of upstream extracellular signals in aged tissues, an increased or altered sensitivity to pro-differentiation cues can further contribute to the age-related functional exhaustion of SCs. Interestingly, previous work has shown that p38 signaling can directly control chromatin structure by targeting key components of the chromatin-modifying machinery, including the Polycomb Repressive Complex (PRC2). Disruption of PRC2-mediated gene repression leads to constitutive de-repression of senescence hallmarks, such as p16, and conversion of aged SCs into senescent cells in geriatric mice (Sousa-Victor et al., 2014Sousa-Victor P. Gutarra S. García-Prat L. Rodriguez-Ubreva J. Ortet L. Ruiz-Bonilla V. Jardí M. Ballestar E. González S. Serrano A.L. et al.Nature. 2014; 506: 316-321Crossref PubMed Scopus (624) Google Scholar). It remains unclear how p38 inhibition could reverse cell cycle arrest associated with cellular senescence (Bernet et al., 2014Bernet J.D. Doles J.D. Hall J.K. Kelly Tanaka K. Carter T.A. Olwin B.B. Nat. Med. 2014; 20: 265-271Crossref PubMed Scopus (362) Google Scholar, Cosgrove et al., 2014Cosgrove B.D. Gilbert P.M. Porpiglia E. Mourkioti F. Lee S.P. Corbel S.Y. Llewellyn M.E. Delp S.L. Blau H.M. Nat. Med. 2014; 20: 255-264Crossref PubMed Scopus (423) Google Scholar), which was previously considered irreversible. A potential explanation arises from the different ages of the mice used in these studies, with p38 inhibition restoring cell cycle activity in pre-senescent, but not senescent, SCs—an effect that has been widely reported in SCs of young mice. The emerging relationships between chromatin structure, signaling pathways, and their potential impact on the irreversible impairment of SCs in geriatric mice deserve future studies. Although the decline in the regenerative potential of aged SCs is well documented, whether this contributes to reduced homeostatic maintenance and progressive reduction in muscle mass in aged individuals—known as sarcopenia—is still a matter of debate. By utilizing an inducible mouse model to selectively ablate Pax7+ SCs, the Peterson team has recently shown that aging-associated sarcopenia is not affected by depletion of SCs, thereby underscoring the low turnover nature of skeletal muscle and pointing to mature myofibers as the direct cellular targets of this chronic process (Fry et al., 2015Fry C.S. Lee J.D. Mula J. Kirby T.J. Jackson J.R. Liu F. Yang L. Mendias C.L. Dupont-Versteegden E.E. McCarthy J.J. Peterson C.A. Nat. Med. 2015; 21: 76-80Crossref PubMed Scopus (281) Google Scholar). However, an increase in fibrosis in aged muscles was observed in these SC-depleted mice. Thus, while these findings indicate that SCs are not directly involved in aged-associated sarcopenia, they also reveal once again the contribution of SCs to the niche/signaling network that regulates muscle homeostasis. This hypothesis is consistent with a function of SCs not only in tissue repair, but also as sources and targets of secreted or cell-contact-mediated signals for coordinated spatio-temporal regulation of the regenerative niche. Further elucidation of the reciprocal interactions between SCs and the other cell types within the niche will improve our understanding of skeletal muscle homeostasis and identify novel targets for pharmacological interventions to counter age-related muscle loss. The interconnected nature of extrinsic and intrinsic changes occurring in SCs during aging suggests that they are both integral components of a self-amplifying molecular network triggered by age-associated perturbations in the SC niche. It is likely that this network evolves into a cell-autonomous and irreversible cause of SC impairment. Whether this potential scenario corresponds to geroconversion will be an interesting matter for future investigation. Ultimately, elucidating the molecular and epigenetic determinants underlying the interplay between extrinsic and intrinsic factor changes in SCs will reveal the nodal points in this network, and such nodes may be amenable to targeted interventions aimed at interrupting the vicious cycle underlying SC aging. In this context, a significant challenge is posed by the intrinsic heterogeneity of SCs. As we move forward, the development of highly sensitive technologies for single-cell analyses will enable us to improve our understanding of SC heterogeneity, how SC populations change with age, and what physiological role this plays in the maintenance of tissue homeostasis. Intriguingly, SC heterogeneity could not only be an intrinsic property of the SC compartment, but may also arise from microenvironmental cues/gradients to which SCs are locally exposed within the tissue. This critical spatial information is lost upon tissue enzymatic digestion and cell isolation, limiting our understanding of SC heterogeneity. The optimization of strategies to perform 3D tissue imaging would enable us to monitor SCs in native tissues, investigate the spatial heterogeneity, and shed light on the relationship between anatomical proximity to specific cell types and establishment of reciprocal functional interactions. These approaches should be complemented with multicolor Cre reporters for clonal lineage tracing in vivo in order to further clarify SC dynamics in living tissues. Finally, understanding the degree to which these animal models of aging and degenerative disease recapitulate human conditions is a major challenge we face. Translational efforts aimed at integrating basic research with patient-oriented studies in the clinic could enable addressing these fundamental questions and further the development of treatments for aging-associated defects in muscle function. This work was supported by US NIH grants R01AR064873, R03 AR063328, and P30 AR061303, Ellison Medical Foundation New Scholar Award AG-NS-0843-11, and the Sanford-Burnham Medical Research Institute startup funds (A.S.) and US NIH grants R01AR056712, R01AR052779, and P30 AR061303 to P.L.P.