Senescent myoblasts exhibit ROS-dependent Akt-mTORC1 dysregulation and are susceptible to reductive stress-induced cell death.

Abstract

Ageing is characterised by the accumulation of senescent cells. Owing to their irreversible cell-cycle arrest, these cells lack the capacity to replenish the stem cell pool and regenerate tissue, while their pro-inflammatory secretome propagates senescence in a paracrine manner. Much of the senescent phenotype has been attributed to dysregulated mTORC1 signalling, a key regulator of protein synthesis implicated in organismal ageing. Nonetheless, the mechanism underlying this dysregulation is poorly understood and limited to a few selected cell types. Here, we show that mTORC1 dysregulation is also a characteristic of senescent muscle precursor cells, and in contrast to reports in other cell types, senescent myoblasts do not rely on lysosomal nutrient liberation to sustain mTORC1 activity. Instead, they appear to depend on the PI3K/Akt pathway, which is upregulated in these cells. Exogenous antioxidants were identified to alleviate PI3K/Akt/mTORC1 signalling, while exogenous ROS has the capacity to activate mTORC1, supporting a model in which ROS acts upstream of this pathway in senescent myoblasts. Moreover, antioxidants were able to suppress the expression of pro-inflammatory cytokines and enhance the differentiation of senescent myoblasts. Interestingly, prolonged antioxidant treatment led to increased cell death in senescent but not proliferating myoblasts, suggesting they are more prone to reductive stress-induced cell death. We propose that, in vitro, the antioxidant capacity of many plant-derived compounds may underlie their reported benefits as therapeutics targeting senescent cells (senotherapeutics). Together, our findings provide novel insights into mTORC1-dependent regulation of the senescent phenotype and highlight the role of redox modulation in senotherapeutic strategies.