Geriatric muscle stem cells switch reversible quiescence into senescence

Sousa‐Victor, Pedro; Gutarra, Susana; García‐Prat, Laura; Rodríguez-Ubreva, Javier; Ortet, Laura; Ruiz‐Bonilla, Vanessa; Jardı́, Mercè; Ballestar, Esteban; González, Susana; Serrano, Antonio L.; Perdiguero, Eusebio; Muñoz‐Cánoves, Pura

doi:10.1038/nature13013

Cited by 789 publications

(844 citation statements)

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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: 89%

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: 89%

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

et al. 2018

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“…Signs of denervation appear as early as 18 months of age in C57Bl/6 mice (Valdez et al ., 2010), although another study reported markers of denervation at 28 but not 22 months of age, even though atrophy was present at 22 months of age (Sousa‐Victor et al ., 2014). Thus, we next asked whether markers of denervation were altered in the 26‐month‐old mice from this study.…”

Section: Discussionmentioning

confidence: 99%

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Walsh¹,

et al. 2015

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SummarySarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with loss of motor neuron innervation, we investigated the potential for the histone deacetylase (HDAC) inhibitor butyrate to modulate age‐related muscle loss. Consistent with previous studies, we found significant loss of hindlimb muscle mass in 26‐month‐old C57Bl/6 female mice fed a control diet. Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hindlimb muscles. Butyrate increased muscle fiber cross‐sectional area and prevented intramuscular fat accumulation in the old mice. In addition to the protective effect on muscle mass, butyrate reduced fat mass and improved glucose metabolism in 26‐month‐old mice as determined by a glucose tolerance test. Furthermore, butyrate increased markers of mitochondrial biogenesis in skeletal muscle and whole‐body oxygen consumption without affecting activity. The increase in mass in butyrate‐treated mice was not due to reduced ubiquitin‐mediated proteasomal degradation. However, butyrate reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity. Our data is the first to show a beneficial effect of butyrate on muscle mass during aging and suggests HDACs contribute to age‐related muscle atrophy and may be effective targets for intervention in sarcopenia and age‐related metabolic disease.

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“…The senescence biomarker p16 INK4a mediates cell cycle arrest through inhibition of cyclin‐dependent kinase 4 and 6 (CDK4/6), but p16 INK4a expression is not required for production of the SASP (Coppe et al., 2011). Furthermore, in vivo evidence suggests that the primary functional consequence of high p16 INK4a expression with aging is to limit the proliferation of specific cell types during homeostasis or in response to injury (Janzen et al., 2006; Krishnamurthy et al., 2006; Liu et al., 2011; Molofsky et al., 2006; Sousa‐Victor et al., 2014). Several groups, however, have suggested cell cycle independent effects of p16 INK4a and CDK4/6 inhibition (Goel et al., 2017; Murakami, Mizoguchi, Saito, Miyasaka & Kohsaka, 2012), and it is unclear whether reduced p16 INK4a expression can protect tissues from age‐related pathologies that are associated with the SASP but not with replicative failure.…”

Section: Introductionmentioning

confidence: 99%

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

et al. 2018

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SummaryCellular senescence drives a functional decline of numerous tissues with aging by limiting regenerative proliferation and/or by producing pro‐inflammatory molecules known as the senescence‐associated secretory phenotype (SASP). The senescence biomarker p16 INK 4a is a potent inhibitor of the cell cycle but is not essential for SASP production. Thus, it is unclear whether p16 INK 4a identifies senescence in hyporeplicative cells such as articular chondrocytes and whether p16 INK 4a contributes to pathologic characteristics of cartilage aging. To address these questions, we examined the role of p16 INK 4a in murine and human models of chondrocyte aging. We observed that p16 INK 4a mRNA expression was significantly upregulated with chronological aging in murine cartilage (~50‐fold from 4 to 18 months of age) and in primary human chondrocytes from 57 cadaveric donors (r 2 = .27, p < .0001). Human chondrocytes exhibited substantial replicative potential in vitro that depended on the activity of cyclin‐dependent kinases 4 or 6 (CDK4/6), and proliferation was reduced in cells from older donors with increased p16 INK 4a expression. Moreover, increased chondrocyte p16 INK 4a expression correlated with several SASP transcripts. Despite the relationship between p16 INK 4a expression and these features of senescence, somatic inactivation of p16 INK 4a in chondrocytes of adult mice did not mitigate SASP expression and did not alter the rate of osteoarthritis (OA) with physiological aging or after destabilization of the medial meniscus. These results establish that p16 INK 4a expression is a biomarker of dysfunctional chondrocytes, but that the effects of chondrocyte senescence on OA are more likely driven by production of SASP molecules than by loss of chondrocyte replicative function.

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Geriatric muscle stem cells switch reversible quiescence into senescence

Cited by 789 publications

References 50 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

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

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Geriatric muscle stem cells switch reversible quiescence into senescence

Cited by 789 publications

References 50 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

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

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Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis