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Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy

Author

Listed:
  • Jing Tao

    (Wuhan University)

  • Yanping Zeng

    (Renmin Hospital of Wuhan University)

  • Bin Dai

    (Wuhan University)

  • Yin Liu

    (Renmin Hospital of Wuhan University)

  • Xiaohan Pan

    (State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences)

  • Li-Qiang Wang

    (Wuhan University
    Wuhan University Shenzhen Research Institute)

  • Jie Chen

    (Wuhan University)

  • Yu Zhou

    (Wuhan University)

  • Zuneng Lu

    (Renmin Hospital of Wuhan University)

  • Liwei Xie

    (State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences)

  • Yi Liang

    (Wuhan University
    Wuhan University Shenzhen Research Institute)

Abstract

The cellular prion protein (PrPC) is required for skeletal muscle function. Here, we report that a higher level of PrPC accumulates in the cytoplasm of the skeletal muscle of six myopathy patients compared to controls. PrPC inhibits skeletal muscle cell autophagy, and blocks myoblast differentiation. PrPC selectively binds to a subset of miRNAs during myoblast differentiation, and the colocalization of PrPC and miR-214-3p was observed in the skeletal muscle of six myopathy patients with excessive PrPC. We demonstrate that PrPC is overexpressed in skeletal muscle cells under pathological conditions, inhibits muscle cell differentiation by physically interacting with a subset of miRNAs, and selectively recruits these miRNAs into its phase-separated condensate in living myoblasts, which in turn enhances liquid–liquid phase separation of PrPC, promotes pathological aggregation of PrP, and results in the inhibition of autophagy-related protein 5-dependent autophagy and muscle bundle formation in myopathy patients characterized by incomplete muscle regeneration.

Suggested Citation

  • Jing Tao & Yanping Zeng & Bin Dai & Yin Liu & Xiaohan Pan & Li-Qiang Wang & Jie Chen & Yu Zhou & Zuneng Lu & Liwei Xie & Yi Liang, 2023. "Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43826-7
    DOI: 10.1038/s41467-023-43826-7
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    References listed on IDEAS

    as
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