2. Academic Validation
  3. mTORC1 induces plasma membrane depolarization and promotes preosteoblast senescence by regulating the sodium channel Scn1a

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

  • Bone Res. 2022 Mar 8;10(1):25. doi: 10.1038/s41413-022-00204-1.
Ajuan Chen  # 1,  Jian Jin  # 2,  Shasha Cheng 3,  Zezheng Liu 1,  Cheng Yang 1,  Qingjing Chen 1,  Wenquan Liang 1,  Kai Li 1,  Dawei Kang 1,  Zhicong Ouyang 1,  Chenfeng Yao 1,  Xiaochun Bai 1 4,  Qingchu Li 1,  Dadi Jin 5,  Bin Huang 6
Affiliations

Affiliations

  • 1 Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Spine Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 2 Department of Spine Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 3 Department of Clinical Laboratory, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 4 Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
  • 5 Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Spine Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. nyorthop@163.com.
  • 6 Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Spine Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. binxue483@163.com.
  • # Contributed equally.
PMID: 35256591 DOI: 10.1038/s41413-022-00204-1
Abstract

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/EBPα, 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.

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