Heterogeneity of skeletal muscle-derived extracellular nanovesicles and role of protein lipidation

Several cell types have the capacity to secrete small vesicles that contain cell-specific collections of proteins, lipids, and genetic material. Research on secreted vesicles has been focusing primarily on the immune system and tumor cells. Recently, we have reported that skeletal muscle (SkM) cell can release nanovesicles. The subcellular architecture of skeletal muscle is very different from that of mononucleated cells, and it is now apparent that preserving muscle structure and function, proper myogenesis and regeneration requires muscle-specific elaborations of known membrane trafficking pathways. For this reason, and on the basis of our findings, we believe that vesicle biogenesis in muscle may differ with that of other mononucleated cells, being sustained by a direct budding of nanovesicle from the plasma membrane. Furthermore, dramatic changes occur during myogenesis, and the C2C12 cell system mimics these events in vitro: migrating myoblasts proliferate (D0), after inducing differentiation they recognize each other (DI), align and adhere (DII) and fuse to form terminally differentiated multinucleated myotubes (DIII), which eventually start to contract at later stages (DVI). During these events profound modifications occur at the cellular (membrane and cytoskeleton) and molecular levels. In this context, two recent papers, from us and another group, showed high heterogeneity of the C2C12-derived nanovesicles, depending upon the differentiation stage of muscle cells. This heterogeneity may reflect differences in the membrane modifications that occur in myocytes (DII) vs. myotubes (DIII-DVI) in a phase that is characterized by a fusion event occurring at the plasma membrane. Here, we investigated how muscle cells generate these vesicles and what are their regulators.