PDGFD: A Dual-Function Regulator That Maintains Myoblast Pool and Fuels Myogenic Differentiation

The role of platelet-derived growth factor D (PDGFD) in mesenchymal cells is well-established, but its specific function in skeletal muscle generation remains unknown. This study reveals for the first time PDGFD’s dual regulatory role in myogenesis: it acts both as a “guardian” maintaining the myoblast pool and as an “initiator” driving myogenic differentiation. Through single-cell RNA sequencing analysis of skeletal muscle from Jiangquan Black pigs, we identified PDGFD as a common candidate gene for both muscle and fat development. In the C2C12 cell model, PDGFD knockdown significantly inhibited cell proliferation and promoted apoptosis, while overexpression enhanced viability and inhibited apoptosis, indicating its critical role in maintaining myoprogenic precursor cell homeostasis. Further studies revealed that PDGFD interference downregulated key myogenic differentiation markers MyoD and MyoG, inhibiting differentiation. Its expression peaked during mid-differentiation (D5), suggesting temporal regulation of differentiation. Interestingly, although PDGFD primarily acts through the PI3K/Akt pathway downstream of PDGFR-β, PDGFD knockdown did not show significant synergistic effects with PI3K/Akt pathway activation in inhibiting differentiation. This suggests PDGFD may specifically regulate myogenic differentiation via an independent or parallel signaling axis. This study not only expands the known functions of PDGFD in muscle biology but also provides new insights into the mechanisms by which growth factors coordinate cell fate decisions.