TRIM32 controls timely cell cycle exit in muscular differentiation through c-Myc down-regulation

Abstract 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 knockout C2C12 murine myoblasts to investigate the impact of Trim32 loss on myogenesis. We found that Trim32 deficiency leads to impaired myogenic signaling and reduced expression of key myogenic regulatory factors ultimately leading to delayed and abnormal myotube formation. Further, we discovered that absence of Trim32 disrupts the transition from proliferation to differentiation by limiting the necessary down-regulation of the proto-oncogene c-Myc, thus delaying and altering the onset of differentation. Interestingly, unlike previous reports that emphasized protein-level regulation, our data reveal that Trim32 regulates c-Myc at mRNA stability level. Contrasting the sustained c-Myc level is able to partially recover the myogenesis defects observed in the absence of Trim32, suggesting that the Trim32–c-Myc axis may represent a promising therapeutic target for treating LGMDR8. Altogether these findings underscore the essential role of Trim32 in muscle regeneration within LGMDR8 pathogenesis.