Abstract
Sphingolipids are not only crucial for membrane architecture but act as critical regulators of cell functions. The bioactive sphingolipid ceramide 1-phosphate (C1P), generated by the action of ceramide kinase, has been reported to stimulate cell proliferation, cell migration and to regulate inflammatory responses via activation of different signaling pathways. We have previously shown that skeletal muscle is a tissue target for C1P since the phosphosphingolipid plays a positive role in myoblast proliferation implying a role in muscle regeneration. Skeletal muscle displays strong capacity of regeneration thanks to the presence of quiescent adult stem cells called satellite cells that upon trauma enter into the cell cycle and start proliferating. However, at present, the exact molecular mechanism by which C1P triggers its mitogenic effect in myoblasts is lacking. Here, we report for the first time that C1P stimulates C2C12 myoblast proliferation via lysophosphatidic acid (LPA) signaling axis. Indeed, C1P subsequently to phospholipase A2 activation leads to LPA1 and LPA3 engagement, which in turn drive Akt (protein kinase B) and ERK1/2 (extracellular signal-regulated kinases 1/2) activation, thus stimulating DNA synthesis. The present findings shed new light on the key role of bioactive sphingolipids in skeletal muscle and provide further support to the notion that these pleiotropic molecules might be useful therapeutic targets for skeletal muscle regeneration.
Highlights
Sphingolipids are crucial for membrane architecture but act as critical regulators of cell functions and are involved in different pathological conditions [1,2]
To characterize the molecular mechanism involved in the proliferative action of ceramide 1-phosphate (C1P) in C2C12 myoblasts, we examined whether C1P-induced activation of ERK1/2 and Akt could be mediated by another G protein-coupled receptor
The inactivation of Gαi and Gαq/11 significantly reduced the phosphorylation of ERK1/2 and Akt induced by 5 min treatment with 15 μM C1P measured by Western blot analysis on myoblast lysates (Figure 1A)
Summary
Sphingolipids are crucial for membrane architecture but act as critical regulators of cell functions and are involved in different pathological conditions [1,2]. The “sphingolipid rheostat” was proposed more than 20 years ago; according to it, the levels of ceramide and sphingosine 1-phosphate (S1P), two interconvertible sphingolipid metabolites, determine the cell fate mediating opposite signaling pathways [3]. S1P intracellularly generated by the enzyme sphingosine kinase (SK), is released by the action of different S1P transporters in the extracellular environment and, in an autocrine/paracrine manner, binds to five differentially expressed G protein-coupled receptors, S1PR (S1P1–5), by the so-called “inside-out” signaling [7]. C1P is a potent regulator of cell migration and of inflammatory responses via direct or PKC-mediated activation of cytosolic phospholipase A2 (cPLA2) [14,15,16,17,18,19]. Plasma concentrations of C1P can vary up to 20 μM [20], being released mainly by macrophages and damaged cells [16,21]
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