CHAMP1 is an essential regulator for human myoblast fusion and muscle development

Human skeletal muscle is composed of myofibers, each formed by the fusion of thousands of individual myoblasts. This process requires tightly regulated expression of muscle-specific fusogens, which confer both efficiency and muscle specificity to cell-cell fusion. Currently, the genetic regulation of this process remains poorly understood. Here, we identify CHAMP1, a chromosome alignment factor, as a surprising upstream activator of human myoblast fusion. Genetic deletion of CHAMP1 in human myoblasts led to profound fusion defects in vitro and in vivo following transplantation. Leveraging genomics approach and protein interaction assays, we uncovered a noncanonical role for CHAMP1 as a transcriptional cofactor for MyoD, directly activating the expression of the key muscle fusogen Myomaker. CHAMP1 mutations in human patients cause developmental delay, hypotonia, and muscle weakness, hallmarks of fusion myopathy that are also observed with Myomaker mutations. Importantly, CHAMP1 patient-derived cells exhibit severe fusion defects that can be fully rescued by restoring Myomaker expression. Structure and function analysis identified C2H2-type zinc finger motifs on CHAMP1 protein that are both necessary and sufficient for interaction with MyoD, activation of Myomaker transcription and human myoblast fusion. These findings highlight the muscle-autonomous role of CHAMP1 in muscle development and disease, and point to therapeutic avenues for treating muscle development defect caused by CHAMP1 mutations.