Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion

The apoptotic event of phosphatidylserine exposure and its recognition by the receptor BAI1 has an unexpected new role as a signal enhancing mouse myoblast fusion, an insight with relevance to some congenital muscle diseases and muscle injury treatments. A signalling function for dead cells Apoptotic cell death occurs throughout development and homeostasis in healthy tissues, including skeletal muscle. This study questions previous assumptions that the resulting dead cells have no beneficial effects. Kodi Ravichandran and colleagues show that during skeletal muscle differentiation in mice, a fraction of precursor muscle cells undergoes apoptosis, and that these cells provide a key signal — phosphatidylserine — that promotes muscle development. The idea that the body may use cell death not only to rid itself of unwanted cells, but also to regulate differentiation adds an intriguing dimension to cell turnover within tissues. Skeletal muscle arises from the fusion of precursor myoblasts into multinucleated myofibres 1 , 2 . Although conserved transcription factors and signalling proteins involved in myogenesis have been identified, upstream regulators are less well understood. Here we report an unexpected discovery that the membrane protein BAI1, previously linked to recognition of apoptotic cells by phagocytes 3 , promotes myoblast fusion. Endogenous BAI1 expression increased during myoblast fusion, and BAI1 overexpression enhanced myoblast fusion by means of signalling through ELMO/Dock180/Rac1 proteins 4 . During myoblast fusion, a fraction of myoblasts within the population underwent apoptosis and exposed phosphatidylserine, an established ligand for BAI1 (ref. 3 ). Blocking apoptosis potently impaired myoblast fusion, and adding back apoptotic myoblasts restored fusion. Furthermore, primary human myoblasts could be induced to form myotubes by adding apoptotic myoblasts, even under normal growth conditions. Mechanistically, apoptotic cells did not directly fuse with the healthy myoblasts, rather the apoptotic cells induced a contact-dependent signalling with neighbours to promote fusion among the healthy myoblasts. In vivo , myofibres from Bai1 −/− mice are smaller than those from wild-type littermates. Muscle regeneration after injury was also impaired in Bai1 −/− mice, highlighting a role for BAI1 in mammalian myogenesis. Collectively, these data identify apoptotic cells as a new type of cue that induces signalling via the phosphatidylserine receptor BA