Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals

Abstract

SUMMARY The functionality of stem cells declines during aging thereby contributing to aging-associated impairments in tissue regeneration and function1. Alterations in developmental pathways have been associated with declines in stem cell function during aging2–6 but the nature of this process remains poorly defined. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in aging7,8. This study identifies an altered epigenetic stress response in muscle stem cells (also known as satellite cells = SCs) of aged compared to young mice. This includes aberrant global and site-specific induction of active chromatin marks in activated SCs from aged mice resulting in the specific induction of Hoxa9 among all Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor separating gene expression of SCs from aged compared to young mice. This includes most of the currently known inhibitors of SC function in aging muscle such as Wnt-, TGFß-, JAK/STAT- and senescence signaling2–4,6. Inhibition of aberrant chromatin activation or deletion of Hoxa9 suffices to improve SC function and muscle regeneration in aged mice, while overexpression of Hoxa9 mimics aging-associated defects in SCs from young mice, which can be rescued by inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated SCs from aged mice, which limits SC function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.

Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer

“…We observed that the levels of both of these genes being lower in muscle of tumor-bearing mice compared to wild type mice. Hoxa9 deregulation in muscle has been studied in the context of aging but not functional limitation and the current study is the first report to show tumor-induced loss of Hoxa9 expression in muscle (33). Our observation on Pax7 depletion in the muscle of tumor-bearing transgenic mice is different from the observed accumulation of Pax7 in muscle under acute cachexia due to block in satellite cell differentiation (24).…”

“…These include Pgc-1β, which is induced by MyoD and alternate NF-κB, and is a negative regulator of canonical NF-κB signaling in skeletal muscle (25,32), Hoxa9, which is typically elevated in aging satellite cells of muscle and its expression is repressed by NF-κB (33,34), and metallothioneins 1 and 2 (Mt1 and Mt2), which control skeletal muscle mass and strength (35). Pgc-1β and Hoxa9 but Mt1 and Mt2 mRNA levels were lower in the skeletal muscle of tumor-bearing mice, which were reversed upon DMAPT treatment (Fig.…”

Rejuvenating Strategies for Stem Cell-Based Therapies in Aging

“…A recent study showed that a site-specific chromatin alteration in aged activated satellite cells leads to the induction of Hox9 and consequent activation of several pathways detrimental for proper satellite cell function. The inhibition of chromatin activation or deletion of Hoxa9 was sufficient to improve satellite cell function and muscle regeneration in old mice, suggesting a causal relation between aberrant epigenetic stress response and functionality of SCs of aged mice (Schworer et al, 2016). The same in depth analysis into causality will have to be applied to the effect of DNA damage in SC aging, considering studies in which defects in DNA repair lead to the accumulation of DNA damage with no effect on satellite cell function (Cousin et al, 2013).…”

Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals

“…In mice, for example, hematopoietic stem cells switch from canonical to non-canonical Wnt signaling (Florian et al, 2013), old dermal fibroblasts gain adipogenic traits (Salzer et al, 2018) and muscle satellite cells activate Wnt signaling, converting them from a myogenic to a fibrogenic lineage (Brack et al, 2007). Satellite cells also activate Hoxa9, which activates Wnt, TGF and JAK/STAT signaling in response to BaCl2-induced muscle injury (Schworer et al, 2016). In aging human brain tissue, too, there is a distinct upregulation of developmental genes (Donertas et al, 2018).…”