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

The cellular prion protein (PrP C ) is required for skeletal muscle function. Here, we report that a higher level of PrP C accumulates in the cytoplasm of the skeletal muscle of six myopathy patients compared to controls. PrP C inhibits skeletal muscle cell autophagy, and blocks myoblast differentiation. PrP C selectively binds to a subset of miRNAs during myoblast differentiation, and the colocalization of PrP C and miR-214-3p was observed in the skeletal muscle of six myopathy patients with excessive PrP C . We demonstrate that PrP C 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 PrP C , 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. The prion protein PrP C is known to play a role in skeletal muscle development and physiology, including in myopathy. Here, the authors report that excess PrP C binds microRNAs that enhance its aggregation, which inhibits autophagy in muscle cells.