Abstract
We reported that RAGE (receptor for advanced glycation end products), a multiligand receptor of the immunoglobulin superfamily expressed in myoblasts, when activated by its ligand amphoterin (HMGB1), stimulates rat L6 myoblast differentiation via a Cdc42-Rac-MKK6-p38 mitogen-activated protein kinase pathway, and that RAGE expression in skeletal muscle tissue is developmentally regulated. We show here that inhibition of RAGE function via overexpression of a signaling deficient RAGE mutant (RAGE delta cyto) results in increased myoblast proliferation, migration, and invasiveness, and decreased apoptosis and adhesiveness, whereas myoblasts overexpressing RAGE behave the opposite, compared with mock-transfected myoblasts. These effects are accompanied by a decreased induction of the proliferation inhibitor, p21(Waf1), and increased induction of cyclin D1 and extent of Rb, ERK1/2, and JNK phosphorylation in L6/RAGE delta cyto myoblasts, the opposite occurring in L6/RAGE myoblasts. Neutralization of culture medium amphoterin negates effects of RAGE activation, suggesting that amphoterin is the RAGE ligand involved in RAGE-dependent effects in myoblasts. Finally, mice injected with L6/RAGE delta cyto myoblasts develop tumors as opposed to mice injected with L6/RAGE or L6/mock myoblasts that do not. Thus, the amphoterin/RAGE pair stimulates myoblast differentiation by the combined effect of stimulation of differentiation and inhibition of proliferation, and deregulation of RAGE expression in myoblasts might contribute to their neoplastic transformation.
Highlights
Myogenesis is a multistep process in which the precursors of myofibers, the myoblasts, first proliferate and differentiate into fusioncompetent cells that fuse with each other to form myotubes [1,2,3]
We reported that receptor for advanced glycation end products (RAGE), a multiligand receptor of the immunoglobulin superfamily expressed in myoblasts, when activated by its ligand amphoterin (HMGB1), stimulates rat L6 myoblast differentiation via a Cdc42Rac-MKK6-p38 mitogen-activated protein kinase pathway, and that RAGE expression in skeletal muscle tissue is developmentally regulated
RAGE Activation in Myoblasts Results in ERK1/2 and Jun NH2-terminal protein kinase (JNK) Inactivation—We have previously shown that the amphoterin/RAGE pair stimulates myogenic differentiation via a Rac1-Cdc42-MKK6-p38 MAPK pathway [16], and data in Figs. 1 and 2 suggest that amphoterin/ RAGE-dependent inhibition of myoblast proliferation and stimulation of myoblast apoptosis might rely on p38 MAPK activation
Summary
Myogenesis is a multistep process in which the precursors of myofibers, the myoblasts, first proliferate and differentiate into fusioncompetent cells that fuse with each other to form myotubes [1,2,3]. We show here that RAGE activation and signaling in myoblasts result in reduced proliferation, migration, invasiveness, and matrix metalloproteinase (MMP) 1 and 2 activity, and increased apoptosis and adhesiveness, and that these effects rely on amphoterin/RAGE-dependent activation of p38 MAPK.
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