Drebrin Links Actin Organization to MRTFA–SRF Signaling During Skeletal Myogenesis

Drebrin is an F-actin side-binding protein previously implicated in myoblast differentiation, but the signaling mechanisms linking drebrin-dependent actin organization to myogenic state transitions remain unclear. Here, we combined transcriptomic prioritization with C2C12 loss-of-function analyses. Drebrin knockdown reduced phalloidin fluorescence and increased DNase I-Alexa Fluor 488 median fluorescence intensity, shifting actin-associated readouts toward a more monomeric state. This was accompanied by increased cytoplasmic MRTFA, reduced nuclear MRTFA and SRF, lower CArG-dependent SMYD1 reporter activity, and decreased expression of SRF-responsive genes. Drebrin knockdown also altered YAP1 abundance and phosphorylation, reduced EdU incorporation and cell-cycle protein expression, increased G0/G1 accumulation, and resulted in approximately 25% fewer cells at 72 h. During differentiation, drebrin knockdown attenuated MyoD, MyoG, and sarcomeric myosin heavy chain (MyHC) expression and impaired myotube formation. Public skeletal-muscle datasets associated DBN1 preferentially with a myogenic transcriptional program, although DBN1/Dbn1 regulation varied across aging and muscle-wasting contexts. These findings support a working model in which drebrin-dependent actin organization contributes to MRTFA–SRF transcriptional competence during myogenic progression. These findings provide a basis for testing the proposed mechanism and for investigating whether drebrin contributes to muscle atrophy in appropriate experimental models.