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

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The cellular prion protein (PrP C ), a glycoprotein existing in membrane-bound and cytoplasmic forms, has functional importance in skeletal muscle, but the mechanism behind the phenomenon remains poorly understood. Here we report that PrP C is overexpressed and located in the cytoplasm of the skeletal muscle of six myopathy patients; cytoplasmic PrP C strongly inhibits skeletal muscle cell autophagy and blocks myoblast differentiation. PrP C selectively binds to a subset of miRNAs during myoblast differentiation, and the co-localization of PrP C with miR-214-3p was clearly observed in the skeletal muscle of six myopathy patients but not in that of four age-matched controls. We demonstrate that PrP C is overexpressed in skeletal muscle cells under pathological conditions and inhibits muscle cell differentiation via physically interacting with a subset of miRNAs to significantly inhibit autophagy-related protein 5-dependent autophagy, and selectively recruits these miRNAs into phase-separated condensates in living myoblasts, which in turn greatly enhances liquid–liquid phase separation (LLPS) of PrP C and results in the subsequent PrP aggregation and muscle bundle formation in myopathy patients characterized by incomplete muscle regeneration. Our findings show how excess PrP C can inhibit muscle cell differentiation via miRNA-enhanced LLPS implicated in myopathy.