<scp>TRIM32</scp> controls timely cell cycle exit in muscular differentiation through downregulation of c‐Myc <scp>mRNA</scp>

Mutations in TRIM32 cause limb-girdle muscular dystrophy recessive 8 (LGMDR8), a neuromuscular disorder primarily affecting the proximal muscles of hips and shoulders. However, the precise pathogenic mechanism remains unclear. In this study, we used Trim32 knock-out C2C12 murine myoblasts to investigate the impact of full Trim32 loss along the myogenesis process. We found that Trim32 deficiency alters global transcriptomics already in the early phases of the differentiation process leading to impaired myogenic signaling, ultimately resulting in delayed and abnormal myotube formation. Following this up, we discovered that lack of Trim32 disrupts the transition from proliferation to differentiation by limiting the necessary downregulation of the proto-oncogene c-Myc, thus delaying and altering the immediate early onset of differentiation. Interestingly, unlike previous reports that emphasized protein-level regulation, our data reveal that, at this precise stage of differentiation, Trim32 regulates the stability of c-Myc at mRNA level. Attenuating c-Myc expression level is able to partially recover the myogenesis defects observed in the absence of Trim32, suggesting that the Trim32-c-Myc axis may represent an essential hub, although likely not the exclusive mechanism, in muscle regeneration within LGMDR8 pathogenesis.