mTORC1 induces plasma membrane depolarization and promotes preosteoblast senescence by regulating the sodium channel Scn1a

作者：Chen, Ajuan; Jin, Jian; Cheng, Shasha; Liu, Zezheng; Yang, Cheng; Chen, Qingjing; Liang, Wenquan; Li, Kai; Kang, Dawei; Ouyang, Zhicong; Yao, Chenfeng; Bai, Xiaochun; Li, Qingchu; Jin, Dadi^*; Huang, Bin^*

来源：Bone Research, 2022, 10(1): 25.

DOI：10.1038/s41413-022-00204-1

• CELLULAR SENESCENCE
• RECEPTOR ACTIVATION
• EXPRESSION
• IDENTIFICATION
• ALPHA
• CALCINEURIN
• SUFFICIENT
• MODULATION
• RAPAMYCIN
• CALCIUM

Senescence impairs preosteoblast expansion and differentiation into functional osteoblasts, blunts their responses to bone formation-stimulating factors and stimulates their secretion of osteoclast-activating factors. Due to these adverse effects, preosteoblast senescence is a crucial target for the treatment of age-related bone loss; however, the underlying mechanism remains unclear. We found that mTORC1 accelerated preosteoblast senescence in vitro and in a mouse model. Mechanistically, mTORC1 induced a change in the membrane potential from polarization to depolarization, thus promoting cell senescence by increasing Ca2+ influx and activating downstream NFAT/ATF3/p53 signaling. We further identified the sodium channel Scn1a as a mediator of membrane depolarization in senescent preosteoblasts. Scn1a expression was found to be positively regulated by mTORC1 upstream of C/EBP alpha, whereas its permeability to Na+ was found to be gated by protein kinase A (PKA)-induced phosphorylation. Prosenescent stresses increased the permeability of Scn1a to Na+ by suppressing PKA activity and induced depolarization in preosteoblasts. Together, our findings identify a novel pathway involving mTORC1, Scn1a expression and gating, plasma membrane depolarization, increased Ca2+ influx and NFAT/ATF3/p53 signaling in the regulation of preosteoblast senescence. Pharmaceutical studies of the related pathways and agents might lead to novel potential treatments for age-related bone loss.

• 单位
  南方医科大学