Using phosphatidylserine exposure on apoptotic cells to stimulate myoblast fusion.

The fusion of myoblasts, the skeletal muscle progenitors, is critical for skeletal muscle formation, function, and repair after muscle injury. Recognition of the phospholipid phosphatidylserine (PtdSer) exposed on certain myoblasts is required during fusion into multinuclear myofibers. Cell surface exposure of PtdSer is also a feature of cells dying through the process of apoptosis. Here, we describe the use of PtdSer exposing apoptotic cells as stimulators of myoblast fusion.

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

Skeletal muscle arises from the fusion of precursor myoblasts into multinucleated myofibres. 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, 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. 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 BAI1 to promote fusion of healthy myoblasts, with important implications for muscle development and repair.

Oxygenated lipids: a mode to WiPE out inflammation?

The immunologically silent clearance of apoptotic cells is crucial for maintaining self-tolerance. In this issue of Immunity, Uderhardt et al. (2012) reveal a mechanism by which lipid oxidation by tissue resident macrophages could inhibit the engulfment of apoptotic cells by inflammatory monocytes.