S100B protein (1) promotes myoblast proliferation and survival and inhibits myoblast differentiation (2,3). We have addressed the questions: 1) whether S100B might participate in myogenesis by virtue of its ability to stimulate myoblast proliferation; and 2) what receptor transduces S100B’s effects in myoblasts. We show here that: 1) clearance of S100B results in enhanced myoblast differentiation in consequence of S100B-induced increase in the cell number; 2) the overall S100B effect on C2C12 and rat and mouse primary myoblasts in differentiation medium varies depending on cell density, the S100B concentration and the duration of treatment of myoblasts with the protein; 3) S100B differentially activates RAGE (receptor for advanced glycation end products) and bFGF receptor 1 (FGFR1) depending on the same parameters as above; 4) S100B interacts with bFGF in high-density (HD) but not low-density (LD) myoblasts; and 5) the S100B/bFGF adduct recruits RAGE and FGFR1 into a RAGE/S100B/bFGF/FGFR1 (trans)complex in apposed cells with resultant blockade of RAGE’s promyogenic signaling and enhancement of FGFR1’s anti-myogenic signaling. We also show that in RAGE-/- primary myoblasts S100B engages FGFR1 via prior interaction with bFGF irrespective of myoblast density, thereby stimulating myoblast proliferation and inhibiting differentiation. The complex regulatory effects of S100B on myoblast differentiation are highlighted by the S100B’s ability to upregulate FGFR1 expression in HD, but not LD myoblasts, by prior complex formation with bFGF, and enhancement of bFGF’s ability to upregulate FGFR1, and to upregulate RAGE expression in LD, but not HD myoblasts in a RAGE-dependent manner. We propose that S100B participates in the myogenic process by differentially activating RAGE and FGFR1in a cell density- and bFGF-dependent manner: whenever an S100B/bFGF complex can form, the resultant enhancement of FGFR1’s mitogenic activity and blockade of RAGE’s promyogenic activity might result in expansion of the myoblast population. By contrast, S100B-dependent RAGE activation in LD myoblasts might help to reduce the fraction of activated myoblasts undergoing quiescence and to increase the fraction of proliferating myoblasts; the myoblast’s final destiny would be dependent on whether sufficient amounts of S100B persist (in which case myoblasts keep proliferating) or S100B is being cleared (in which case myoblasts reduce their proliferation rate and differentiate and/or attain a quiescent status). 1. Donato R et al (2008) Biochim Biophys Acta, DOI: 10.1016/j.bbamcr.2008.11.009; 2. Sorci G et al (2003) Mol Cell Biol 23:4870-81; 3. Riuzzi F et al (2006) J Cell Physiol 207:461-70.

S100B protein differentially regulates myoblast differentiation via direct binding to RAGE and bFGF-mediated activation of FGFR1 in low-density and high-density cultures, respectively

DONATO, Rosario Francesco;RIUZZI, Francesca;SORCI, Guglielmo
2009

Abstract

S100B protein (1) promotes myoblast proliferation and survival and inhibits myoblast differentiation (2,3). We have addressed the questions: 1) whether S100B might participate in myogenesis by virtue of its ability to stimulate myoblast proliferation; and 2) what receptor transduces S100B’s effects in myoblasts. We show here that: 1) clearance of S100B results in enhanced myoblast differentiation in consequence of S100B-induced increase in the cell number; 2) the overall S100B effect on C2C12 and rat and mouse primary myoblasts in differentiation medium varies depending on cell density, the S100B concentration and the duration of treatment of myoblasts with the protein; 3) S100B differentially activates RAGE (receptor for advanced glycation end products) and bFGF receptor 1 (FGFR1) depending on the same parameters as above; 4) S100B interacts with bFGF in high-density (HD) but not low-density (LD) myoblasts; and 5) the S100B/bFGF adduct recruits RAGE and FGFR1 into a RAGE/S100B/bFGF/FGFR1 (trans)complex in apposed cells with resultant blockade of RAGE’s promyogenic signaling and enhancement of FGFR1’s anti-myogenic signaling. We also show that in RAGE-/- primary myoblasts S100B engages FGFR1 via prior interaction with bFGF irrespective of myoblast density, thereby stimulating myoblast proliferation and inhibiting differentiation. The complex regulatory effects of S100B on myoblast differentiation are highlighted by the S100B’s ability to upregulate FGFR1 expression in HD, but not LD myoblasts, by prior complex formation with bFGF, and enhancement of bFGF’s ability to upregulate FGFR1, and to upregulate RAGE expression in LD, but not HD myoblasts in a RAGE-dependent manner. We propose that S100B participates in the myogenic process by differentially activating RAGE and FGFR1in a cell density- and bFGF-dependent manner: whenever an S100B/bFGF complex can form, the resultant enhancement of FGFR1’s mitogenic activity and blockade of RAGE’s promyogenic activity might result in expansion of the myoblast population. By contrast, S100B-dependent RAGE activation in LD myoblasts might help to reduce the fraction of activated myoblasts undergoing quiescence and to increase the fraction of proliferating myoblasts; the myoblast’s final destiny would be dependent on whether sufficient amounts of S100B persist (in which case myoblasts keep proliferating) or S100B is being cleared (in which case myoblasts reduce their proliferation rate and differentiate and/or attain a quiescent status). 1. Donato R et al (2008) Biochim Biophys Acta, DOI: 10.1016/j.bbamcr.2008.11.009; 2. Sorci G et al (2003) Mol Cell Biol 23:4870-81; 3. Riuzzi F et al (2006) J Cell Physiol 207:461-70.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11391/41543
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact