M-cadherin regulates the formation of adherens junctions and secondary myofibers during fetal myogenesis to determine adult myofiber number and muscle mass

Cadherin-mediated adhesion of skeletal muscle stem cells within their niche is necessary for normal adult muscle maintenance and regeneration; however, the role of cadherins in regulating muscle development and growth has not yet been elucidated. Here, we show that M-cadherin protein is localized to adherens junctions in developing muscle and that deletion of Cdh15, the gene encoding M-cadherin, results in the loss of adherens junctions in fetal mouse muscle. This loss of adherens junctions is associated with reduced secondary myofiber formation, ultimately resulting in reduced adult myofiber number and muscle mass. Concordantly, via large-scale exome sequencing, we found that humans with predicted loss-of-function variants in the CDH15 gene had significantly reduced lean mass, indicating that M-cadherin functions to regulate muscle mass in both mice and humans. Overall, these data highlight a previously unrecognized role of M-cadherin in controlling fetal myofiber formation and establishment of adult muscle mass.