Notch-Mediated Restoration of Regenerative Potential to Aged Muscle

Conboy, Irina M.; Conboy, Michael J.; Smythe, Gayle M.; Rando, Thomas A.

doi:10.1126/science.1087573

Cited by 955 publications

(1,022 citation statements)

References 21 publications

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“…In line with previous studies (Bernet et al, 2014; Brack et al, 2007; Chakkalakal, Jones, Basson, & Brack, 2012; Conboy, Conboy, Smythe, & Rando, 2003; Cosgrove et al, 2014; Lee et al, 2013; Shavlakadze, McGeachie, & Grounds, 2010; Sousa‐Victor et al, 2014), we found that muscle regeneration after cardiotoxin (CTX) injury is delayed in male aged animals (Figure 1a–c), as shown by the distribution of the cross‐sectional area (CSA; Supporting information Figure S1A–D), the mean CSA (Figure 1b), the increase in necrotic fiber content at Day 8 post‐CTX (Figure 1c), and the muscle mass alterations during the regeneration process (Figure 1d).…”

Section: Introduction Results Discussionsupporting

confidence: 91%

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

et al. 2018

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Tissue regeneration is a highly coordinated process with sequential events including immune cell infiltration, clearance of damaged tissues, and immune‐supported regrowth of the tissue. Aging has a well‐documented negative impact on this process globally; however, whether changes in immune cells per se are contributing to the decline in the body’s ability to regenerate tissues with aging is not clearly understood. Here, we set out to characterize the dynamics of macrophage infiltration and their functional contribution to muscle regeneration by comparing young and aged animals upon acute sterile injury. Injured muscle of old mice showed markedly elevated number of macrophages, with a predominance for Ly6Chigh pro‐inflammatory macrophages and a lower ratio of the Ly6Clow repair macrophages. Of interest, a recently identified repair macrophage‐derived cytokine, growth differentiation factor 3 (GDF3), was markedly downregulated in injured muscle of old relative to young mice. Supplementation of recombinant GDF3 in aged mice ameliorated the inefficient regenerative response. Together, these results uncover a deficiency in the quantity and quality of infiltrating macrophages during aging and suggest that in vivo administration of GDF3 could be an effective therapeutic approach.

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Section: Introduction Results Discussionsupporting

confidence: 91%

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

et al. 2018

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“…In human muscle, in vivo studies quantifying numbers of muscle satellite cells by immunostaining for panels of markers indicate modest decreases in number (Renault et al, 2002;Carlson et al, 2009). Studies in rodents, however, show opposite results, with increased numbers of muscle satellite cells during aging in rats (Gibson and Schultz, 1983) and either a decrease (Bockhold et al, 1998) or no significant difference in aging mice (Conboy et al, 2003). Changes in muscle satellite cell number with age may depend on the species and genetic background, the type of muscle assessed and the age at which the measurements are carried out.…”

Section: Defects In Number In Aging Stem Cellsmentioning

confidence: 99%

Epigenetic regulation of aging stem cells

2011

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“…However, in the case of aged muscle, the regenerative cascade is characterized by a shift from functional myofiber repair toward increased extracellular matrix (ECM) deposition (Carlson, 1995; Grounds, 1998). This impaired regeneration, among other things, appears to be attributed to dysfunction in MuSC proliferative capacity (Conboy et al ., 2003) and MuSC divergence toward a fibrogenic lineage (Brack et al ., 2007). …”

Section: Introductionmentioning

confidence: 99%

Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion

et al. 2017

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SummaryAge‐related declines in skeletal muscle regeneration have been attributed to muscle stem cell (MuSC) dysfunction. Aged MuSCs display a fibrogenic conversion, leading to fibrosis and impaired recovery after injury. Although studies have demonstrated the influence of in vitro substrate characteristics on stem cell fate, whether and how aging of the extracellular matrix (ECM) affects stem cell behavior has not been investigated. Here, we investigated the direct effect of the aged muscle ECM on MuSC lineage specification. Quantification of ECM topology and muscle mechanical properties reveals decreased collagen tortuosity and muscle stiffening with increasing age. Age‐related ECM alterations directly disrupt MuSC responses, and MuSCs seeded ex vivo onto decellularized ECM constructs derived from aged muscle display increased expression of fibrogenic markers and decreased myogenicity, compared to MuSCs seeded onto young ECM. This fibrogenic conversion is recapitulated in vitro when MuSCs are seeded directly onto matrices elaborated by aged fibroblasts. When compared to young fibroblasts, fibroblasts isolated from aged muscle display increased nuclear levels of the mechanosensors, Yes‐associated protein (YAP)/transcriptional coactivator with PDZ‐binding motif (TAZ), consistent with exposure to a stiff microenvironment in vivo. Accordingly, preconditioning of young fibroblasts by seeding them onto a substrate engineered to mimic the stiffness of aged muscle increases YAP/TAZ nuclear translocation and promotes secretion of a matrix that favors MuSC fibrogenesis. The findings here suggest that an age‐related increase in muscle stiffness drives YAP/TAZ‐mediated pathogenic expression of matricellular proteins by fibroblasts, ultimately disrupting MuSC fate.

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Notch-Mediated Restoration of Regenerative Potential to Aged Muscle

Cited by 955 publications

References 21 publications

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

Epigenetic regulation of aging stem cells

Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion

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