Sphingosine 1‐phosphate regulates myogenic differentiation: a major role for S1P ₂ receptor

Abstract

In this study a novel biological activity of sphingosine 1-phosphate (S1P) in C2C12 myoblasts was identified. In these cells the bioactive lipid profoundly regulated myogenesis exerting an antimitogenic activity, by reducing serum-induced cell proliferation, and acting as powerful prodifferentiating agent by enhancing the expression of myogenic differentiation markers such as myogenin, myosin heavy chain, and caveolin-3. The S1P-dependent diminution of serum-induced labeled thymidine incorporation was abrogated by antisense oligodeoxyribonucleotides (ODN) to S1P2, but not to S1P1 or S1P3 receptor, also expressed in C2C12 cells, implicating S1P2 in the biological response. Using antisense ODN and short interfering RNA treatment, we highlighted the key role played by S1P2 in the S1P-dependent induction of muscle-specific gene products. Notably, S1P2 overexpression increased the content of myogenic markers and hastened the onset of differentiated muscle phenotype in comparison with control cells. Cell treatment with pertussis toxin did not affect the biological responses to S1P, ruling out the involvement of Gi-mediated events in the signaling promoted by the sphingolipid. Among the various signaling pathways activated by S1P, the activation of ERK1/ERK2 and p38 MAPK, both identified as downstream effectors of S1P2, was required for the inhibition of cell proliferation and the stimulation of myogenic differentiation, respectively.

Tumor necrosis factor‐α exerts pro‐myogenic action in C2C12 myoblasts via sphingosine kinase/S1P2 signaling

“…Since SphK is required for myogenesis [7], and exogenous S1P is pro-myogenic via S1P 2 -dependent activation of p38 MAPK [6], it is tempting to speculate that SphK/S1P 2 axis plays a role Fig. 4.…”

“…In view of the recognized ability of TNFa to regulate SphK [8][9][10] and the pro-myogenic role exerted by S1P and SphK in myoblasts [6,7], the effect of TNFa at low dose on SphK was then examined. Data illustrated in Fig.…”

Modulation of the expression of sphingosine 1-phosphate 2 receptors regulates the differentiation of pre-adipocytes

“…Studies have been conducted on the effects of S1P on cell differentiation. S1P has been reported to act as a regulator of osteoclast differentiation (24) in addition to myogenic differentiation (18,25). It is widely accepted that S1P and the S1P 2 receptor are associated with myogenic differentiation of mesenchymal stem cells through G(i)-coupled S1P receptor interactions.…”

“…During early stages of CNS development, Modulation of the expression of sphingosine 1-phosphate 2 receptors regulates the differentiation of pre-adipocytes S1P 2 receptors have been identified to be expressed in young animals and differentiate into neuronal cells (16). In addition, S1P 2 receptors upregulate myogenic differentiation of myoblast cells and adipose-derived mesenchymal stem cells (10,17,18). However, to date, the effect of S1P-mediated S1P 2 receptors on adipogenic differentiation has remained to be fully elucidated.…”

Sphingosine-1-phosphate: distribution, metabolism and role in the regulation of cellular functions

“…S1P receptors have been detected in skeletal muscle [117]. A S1P signaling pathway via S1P(2)R and activation of ERK1/ERK2 and p38 MAPK appeared to be important for the suppression of cell proliferation and stimulation of myogenic differentiation [118]. Up-regulation of gap junctional protein connexin-43 evoked by S1P may be involved in intercellular communication during the early phases of myoblast differentiation and down-regulation of connexin-43 blocked myogenesis [119].…”