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

Aim: Sarcopenia is associated with metabolic dysregulation, yet the molecular mediators remain poorly defined. This study aimed to identify relevant regulators of muscle mass and to elucidate the role and underlying mechanism of progranulin in skeletal muscle protein synthesis.

Methods: We combined transcriptomic profiling of muscles from high-fat diet-fed mice with human genetic data from the HugeAMP Type 2 Diabetes Knowledge Portal to identify potential regulators. Clinically, 172 participants were stratified into low muscle mass (LMM) and normal muscle mass (NMM) groups according to the Asian Working Group for Sarcopenia criteria, and serum progranulin was measured. In vitro, recombinant progranulin was applied to L6 myoblasts to assess proliferation and differentiation and to differentiated L6 myotubes to evaluate protein synthesis and mTOR/S6K/S6 signaling. We performed shRNA-mediated knockdown of Ephrin type-A receptor 2 (EphA2), a functional progranulin receptor, to determine its impact on progranulin-induced effects in L6 myotubes.

Results: Transcriptomics identified Grn as a top downregulated gene in metabolically stressed muscle. Clinically, serum progranulin levels were significantly lower in the LMM group than the NMM group (280.71 ± 148.09 vs. 378.96 ± 139.65 ng/mL, p < 0.001). In vitro, progranulin did not affect the proliferation or differentiation of L6 myoblasts. However, it dose-dependently enhanced protein synthesis and increased phosphorylation of mTOR, S6K, and S6 in L6 myotubes. Furthermore, EphA2 knockdown attenuated progranulin-induced protein synthesis and phosphorylation of mTOR, S6K, and S6.

Conclusion: Progranulin acts as a novel regulator of skeletal muscle metabolism, which enhances protein synthesis through EphA2-mediated activation of the mTOR signaling cascade.

EphA2; progranulin; protein synthesis; sarcopenia; skeletal muscle.