Sphingosine kinase/sphingosine 1-phosphate axis: a new player for insulin-like growth factor-1-induced myoblast differentiation.
Sphingosine kinase/sphingosine 1-phosphate axis: a new player for insulin-like growth factor-1-induced myoblast differentiation.
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DOI：
10.1186/2044-5040-2-15
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发表时间：
2012-07-12
期刊：
影响因子：
4.9
通讯作者：
Bruni P
中科院分区：
文献类型：
--
作者：
Bernacchioni C;Cencetti F;Blescia S;Donati C;Bruni P
胰岛素样生长因子-1 (IGF-1) 是骨骼肌祖细胞最重要的生理调节因子，负责成人骨骼肌再生。 IGF-1 影响骨骼肌细胞生物学多个方面（例如增殖、分化、存活和运动）的能力已得到广泛认可，但其复杂生物作用所涉及的分子机制尚未完全明确。由于 1-磷酸鞘氨醇 (S1P) 最近已成为骨骼肌再生的关键参与者，我们研究了鞘氨醇激酶 (SK)/S1P 受体轴对小鼠成肌细胞中 IGF-1 生物学效应的可能参与。 RNA 干扰、化学抑制和免疫荧光方法用于评估 SK/S1P 轴对 C2C12 成肌细胞中 IGF-1 的生肌和有丝分裂作用的作用。我们发现 IGF-1 可以增加小鼠成肌细胞的 SK 活性。生长因子的作用不涉及 SK1 或 SK2 的转录调节，因为两种异构体的蛋白质含量不受影响；相反，IGF-1 提高了 SK 活性形式的比例。此外，IGF-1 通过 SK 激活诱导的 S1P2 受体反式激活似乎与生长因子的生肌作用有关。事实上，当 SK 活性受到药理学抑制，或者 SK1 或 SK2 被特异性沉默，或者 S1P2 受体下调时，IGF-1 在成肌细胞中的促分化作用就会受到损害。此外，在这项研究中，我们表明 IGF-1 通过 SK 激活反式激活 S1P1/S1P3 受体，并且该分子事件负向调节生长因子引起的有丝分裂效应，因为 S1P1 或 S1P3 受体的特异性沉默会增加 IGF-1 诱导的细胞增殖。我们证明了 SK/S1P 轴在应对 IGF-1 成肌细胞攻击时的双重作用，这可能对于调节这种生长因子的生物效应很重要。这些发现为理解 IGF-1 调节骨骼肌再生的机制提供了新的信息。
Insulin-like growth factor-1 (IGF-1) is the most important physiological regulator of skeletal muscle progenitor cells, which are responsible for adult skeletal muscle regeneration. The ability of IGF-1 to affect multiple aspects of skeletal muscle cell biology such as proliferation, differentiation, survival and motility is well recognized, although the molecular mechanisms implicated in its complex biological action are not fully defined. Since sphingosine 1-phosphate (S1P) has recently emerged as a key player in skeletal muscle regeneration, we investigated the possible involvement of the sphingosine kinase (SK)/S1P receptor axis on the biological effects of IGF-1 in murine myoblasts. RNA interference, chemical inhibition and immunofluorescence approaches were used to assess the role of the SK/S1P axis on the myogenic and mitogenic effects of IGF-1 in C2C12 myoblasts. We show that IGF-1 increases SK activity in mouse myoblasts. The effect of the growth factor does not involve transcriptional regulation of SK1 or SK2, since the protein content of both isoforms is not affected; rather, IGF-1 enhances the fraction of the active form of SK. Moreover, transactivation of the S1P2 receptor induced by IGF-1 via SK activation appears to be involved in the myogenic effect of the growth factor. Indeed, the pro-differentiating effect of IGF-1 in myoblasts is impaired when SK activity is pharmacologically inhibited, or SK1 or SK2 are specifically silenced, or the S1P2 receptor is downregulated. Furthermore, in this study we show that IGF-1 transactivates S1P1/S1P3 receptors via SK activation and that this molecular event negatively regulates the mitogenic effect elicited by the growth factor, since the specific silencing of S1P1 or S1P3 receptors increases cell proliferation induced by IGF-1. We demonstrate a dual role of the SK/S1P axis in response to myoblast challenge with IGF-1, that likely is important to regulate the biological effect of this growth factor. These findings add new information to the understanding of the mechanism by which IGF-1 regulates skeletal muscle regeneration.
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