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Updated: Jul 9, 2025
Direct Reprogramming of Human Fibroblasts into Myoblasts to Investigate Therapies for Neuromuscular Disorders
Published on: April 3, 2021
Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid-liquid phase separation implicated in
Jing Tao1, Yanping Zeng2, Bin Dai1
1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China.
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.
Insights
Cellular prion protein (PrPC) accumulation in skeletal muscle inhibits cell differentiation and autophagy. This study reveals PrPC
Area of Science:
- Molecular Biology
- Cellular Biology
- Neuroscience
- Muscle Physiology
Background:
- The cellular prion protein (PrPC) plays a crucial role in skeletal muscle function.
- Dysregulation of PrPC is implicated in various cellular processes.
- Skeletal muscle disorders often involve impaired differentiation and autophagy.
Purpose of the Study:
- To investigate the role of PrPC accumulation in skeletal muscle myopathies.
- To elucidate the molecular mechanisms by which PrPC affects myoblast differentiation and autophagy.
- To identify specific molecular interactions involving PrPC in pathological muscle conditions.
Main Methods:
- Comparative analysis of PrPC levels in skeletal muscle from myopathy patients and controls.
- In vitro studies on myoblast differentiation and autophagy inhibition by PrPC.
- MicroRNA (miRNA) profiling and interaction studies with PrPC.
- Confocal microscopy to observe PrPC and miRNA colocalization.
Main Results:
- Elevated cytoplasmic PrPC levels were observed in skeletal muscle of myopathy patients.
- PrPC was found to inhibit myoblast differentiation and autophagy.
- PrPC selectively binds to specific miRNAs, including miR-214-3p, which colocalized with PrPC in patient muscle.
- PrPC overexpression leads to pathological aggregation and impaired muscle regeneration.
Conclusions:
- PrPC overexpression in skeletal muscle under pathological conditions inhibits differentiation and autophagy.
- PrPC interacts with specific miRNAs, sequestering them in phase-separated condensates, thereby disrupting normal cellular functions.
- These findings highlight PrPC as a key factor in the pathogenesis of myopathies characterized by incomplete muscle regeneration.
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