Increased Wnt Signaling During Aging Alters Muscle Stem Cell Fate and Increases Fibrosis

Brack, Andrew S.; Conboy, Michael J.; Roy, Sudeep; Lee, Mark; Kuo, Calvin J.; Keller, Charles; Rando, Thomas A.

doi:10.1126/science.1144090

Cited by 1,338 publications

(1,415 citation statements)

References 17 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: 92%

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: 92%

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

et al. 2018

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“…[5][6][7] Conversely, both dystrophic and aged skeletal muscle display activated WNT signaling resulting in increased muscle fibrosis. 8 In DMD, a similar dysregulation of the transcriptional-level WNT signaling components has been reported. 9 MicroRNAs (miRNAs) have been shown to have an essential role in muscle development, differentiation, and disease.…”

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confidence: 54%

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

et al. 2013

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In patients with Duchenne muscular dystrophy (DMD), the absence of a functional dystrophin protein results in sarcolemmal instability, abnormal calcium signaling, cardiomyopathy, and skeletal muscle degeneration. Using the dystrophin-deficient sapje zebrafish model, we have identified microRNAs (miRNAs) that, in comparison to our previous findings in human DMD muscle biopsies, are uniquely dysregulated in dystrophic muscle across vertebrate species. MiR-199a-5p is dysregulated in dystrophindeficient zebrafish, mdx 5cv mice, and human muscle biopsies. MiR-199a-5p mature miRNA sequences are transcribed from stem loop precursor miRNAs that are found within the introns of the dynamin-2 and dynamin-3 loci. The miR-199a-2 stem loop precursor transcript that gives rise to the miR-199a-5p mature transcript was found to be elevated in human dystrophic muscle. The levels of expression of miR-199a-5p are regulated in a serum response factor (SRF)-dependent manner along with myocardin-related transcription factors. Inhibition of SRF-signaling reduces miR-199a-5p transcript levels during myogenic differentiation. Manipulation of miR-199a-5p expression in human primary myoblasts and myotubes resulted in dramatic changes in cellular size, proliferation, and differentiation. MiR-199a-5p targets several myogenic cell proliferation and differentiation regulatory factors within the WNT signaling pathway, including FZD4, JAG1, and WNT2. Overexpression of miR-199a-5p in the muscles of transgenic zebrafish resulted in abnormal myofiber disruption and sarcolemmal membrane detachment, pericardial edema, and lethality. Together, these studies identify miR-199a-5p as a potential regulator of myogenesis through suppression of WNT-signaling factors that act to balance myogenic cell proliferation and differentiation.

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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%

“…in vitro systems have confirmed the exquisite sensitivity of stem cells to extrinsic mechanical and structural cues emanating from the surrounding microenvironment (Engler et al ., 2006; Gilbert et al ., 2010). In vivo studies investigating modulation of the microenvironment have similarly demonstrated effects on the proliferation, migration, and myogenicity of both endogenous (Conboy et al ., 2005; Brack et al ., 2007) and transplanted MuSCs (Palermo et al ., 2005; Gargioli et al ., 2008; Ambrosio et al ., 2009, 2010; Distefano et al ., 2013), effects that ultimately affect muscle regeneration and function (Ambrosio et al ., 2009; Distefano et al ., 2013). Still, little is known about how aging affects properties of the skeletal muscle ECM and how such alterations may affect MuSC fate.…”

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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Increased Wnt Signaling During Aging Alters Muscle Stem Cell Fate and Increases Fibrosis

Cited by 1,338 publications

References 17 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

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

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

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