Senescent cells are a mechanism of aging, but also a mechanism of regeneration. When entering a senescent state, a cell shuts down replication and begins to secrete a mix of inflammatory and other signals, rousing the immune system and altering the behavior of surrounding cells. In addition to the other ways in which cells become senescent, in response to the Hayflick limit on cellular replication, or to potentially cancerous DNA damage, senescent cells also arise in response to injury. Their secretions help to guide the complicated dance of immune cells, stem cells, and somatic cells that takes place during the consequent regeneration. Afterwards, the senescent cells self-destruct via apoptosis, or are destroyed by the immune system.
Unfortunately, it is never the case that all senescent cells are destroyed. Those resulting from injury are a tiny fraction of the somatic cells that become senescent on reaching the Hayflick limit, but we can still hypothesize that cellular senescence is important in, say, the way in which joint injuries can become lasting disabilities, or bring on early arthritis. As lingering senescent cells accumulate in tissues, secreted signals that are beneficial in the short term become instead the cause of chronic inflammation and disruption of normal tissue function. Senescent cells are thus a cause of aging, and we will all benefit from therapies capable of removing those that linger in our bodies.
Today’s open access paper is an example of the widespread and ongoing deeper investigations of the biochemistry of senescent cells. The present growth of a biotechnology development community focused on producing therapies to destroy senescent cells helps to ensure that ever more funding is provided for fundamental research. In the present environment any novel examination of cellular senescence might turn up mechanisms that can give rise to startup biotechnology companies, which tends to encourage more such research. In this case the focus is on one of the many protein interactions underlying the behavior of senescent cells in muscle regeneration and aging.
Skeletal muscle acts as a key regulator of systemic aging in humans. The negative effects of senescence on skeletal muscle were recognized since loss of muscle mass during aging results in frailty and decrease in life qualify. Reduction of quiescent muscle stem cells through senescence leads to the decline in muscle regeneration in aged mice. It is noteworthy that the senescence-associated secretory phenotype (SASP) plays a key role in regulating the beneficial action of senescence during tissue regeneration.
Notably, transient, but not aberrant or prolonged, exposure to the SASP enhances stemness and induces cell plasticity, both of which are beneficial for regeneration. However, a p53-dependent persistent senescence impairs muscle repair, indicating that the accurate temporal regulation of p53-induced senescence is pivotal for ensuring accomplishment of muscle regeneration. Interestingly, a recent report showed that activated Notch-p53 is important for the expansion of muscle stem cell in aged animal. Moreover, p53 also regulates the balance between myoblast differentiation and quiescence. These findings indicate that the roles of p53 in modulating muscle homeostasis are complicated.
Here, we found that Hsp90β, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA-seq analysis disclosed a transcriptional elevation of p21 in Hsp90β-depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90β in myoblasts resulted in p53-dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90β preferentially bound to wild-type p53 and modulated its degradation via a proteasome-dependent manner. Moreover, Hsp90β interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53-p21 axis was negatively correlated with Hsp90β in aged mice muscle. Consistently, administration of 17-AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury-induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90β in regulating p53 stability to suppress senescence both in vitro and in vivo.