Hippo-YAP1/TAZ-TEAD signaling coordinates myoblast fusion and sarcomere assembly in skeletal muscle development

Hippo-YAP1/TAZ-TEAD signaling has been implicated in myogenesis, but how this pathway coordinates myoblast fusion with sarcomere assembly in vivo is poorly understood. Here we dissect the roles of YAP1 and TAZ in skeletal muscle development of mice using muscle specific single and double knockouts combined with multi omics and regulatory analysis. Muscle specific double knockout of Yap1 and Wwtr1 (Taz) causes perinatal lethality with failure of myofiber maturation, characterized by secondary myotubes that remain arrested in small, doughnut like configurations and by disorganized, incomplete sarcomeres. Developmental analysis reveals non redundant functions of YAP1 and TAZ in coordinating primary and secondary myogenesis and establishing fiber type architecture. Integrative RNA seq, TEAD1/TEAD4 ChIP seq and single cell ATAC seq identify a conserved YAP1/TAZ-TEAD transcriptional program that jointly regulates myoblast fusion genes (Mymk, Mymx) and sarcomere genes (Myh3, Ttn) via MCAT containing regulatory elements. Together, these findings establish Hippo-YAP1/TAZ-TEAD signaling as a central coordinator of myoblast fusion and sarcomere assembly in skeletal muscle, providing a mechanistic framework for Hippo dependent control of tissue morphogenesis.