Towards the identification of the membrane receptor(s) transducing S100B effects on myoblasts.

Embryonic myogenesis and muscle regeneration are tightly controlled processes resulting from a timely and balanced succession of proliferation/migration and differentiation of myoblasts and satellite cells (SCs). Some extracellular factors activate myoblasts/SCs and stimulate their proliferation/migration, while other factors stimulate myoblast/SC differentiation. S100B is a Ca2+-modulated protein of the EF-hand type that activates quiescent L6, C2C12 and primary myoblasts and stimulates their proliferation and migration (Mol Cell Biol 23:4870-4881, 2003; J Cell Phsyiol 207:461-470, 2006). These effects result in stimulation of myoblast differentiation if myoblasts have been seeded at a low density and are being treated with S100B for no longer than 24 h. Under these conditions, S100B binds to RAGE (receptor for advanced glycation end products), but not FGFR1, c-Met or N-cadherin, thereby activating ERK1/2 and p38 MAPK and upregulating Myf5 and MyoD. However, a long-term treatment with S100B results in inhibition of myoblast differentiation due to chronic stimulation of proliferation, irrespective of the initial myoblast density. Under these conditions, S100B binds to RAGE and FGFR1, but not c-Met, and promotes the formation of a ternary complex made of RAGE, FGFR1 and oligomeric S100B. Thus, S100B binding to RAGE in low-density myoblasts stimulates proliferation via ERK1/2 activation and primes myoblasts to differentiation via concomitant activation of p38 MAPK. By contrast, S100B-dependent FGFR1 activation in high density myoblasts results in proliferation via ERK1/2 activation. As S100B binding to RAGE under these conditions does not result in p38 MAPK activation, we speculate that the formation of a ternary S100B-FGFR1-RAGE complex results in inactivation of RAGE.