Progranulin Regulates Protein Synthesis in Myocytes Through an Ephrin Type A Receptor 2-Dependent Pathway

Area of Science:

• Molecular Biology
• Metabolism
• Skeletal Muscle Physiology

Background:

• Sarcopenia, characterized by muscle loss, is linked to metabolic issues, but the underlying molecular mechanisms are unclear.
• Identifying molecular mediators is crucial for understanding and treating sarcopenia and metabolic dysregulation.

Purpose of the Study:

• To identify regulators of muscle mass and elucidate progranulin's role in skeletal muscle protein synthesis.
• To investigate the mechanism by which progranulin influences muscle metabolism.

Main Methods:

• Transcriptomic analysis of mouse muscle and human genetic data identified potential regulators.
• Clinical study measured serum progranulin in participants with low versus normal muscle mass.
• In vitro experiments assessed progranulin's effects on myoblast proliferation, differentiation, and myotube protein synthesis, including mTOR signaling and EphA2 receptor function.

Main Results:

• Progranulin (Grn) was downregulated in metabolically stressed muscle.
• Serum progranulin was significantly lower in individuals with low muscle mass (LMM) compared to normal muscle mass (NMM).
• Progranulin dose-dependently enhanced protein synthesis and mTOR signaling in myotubes, an effect dependent on the EphA2 receptor.

Conclusions:

• Progranulin is a novel regulator of skeletal muscle metabolism.
• Progranulin enhances skeletal muscle protein synthesis via EphA2-mediated activation of the mTOR signaling pathway.
• These findings suggest progranulin's potential as a therapeutic target for sarcopenia.