Genetics and Development Department, Institut Cochin, Université Paris Descartes, CNRS UMR 8104, Paris, France.
PLoS One. 2009 Dec 30;4(12):e8509. doi: 10.1371/journal.pone.0008509.
Intramyocellular lipid accumulation is strongly related to insulin resistance in humans, and we have shown that high glucose concentration induced de novo lipogenesis and insulin resistance in murin muscle cells. Alterations in Wnt signaling impact the balance between myogenic and adipogenic programs in myoblasts, partly due to the decrease of Wnt10b protein. As recent studies point towards a role for Wnt signaling in the pathogenesis of type 2 diabetes, we hypothesized that activation of Wnt signaling could play a crucial role in muscle insulin sensitivity.
METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that SREBP-1c and Wnt10b display inverse expression patterns during muscle ontogenesis and regeneration, as well as during satellite cells differentiation. The Wnt/beta-catenin pathway was reactivated in contracting myotubes using siRNA mediated SREBP-1 knockdown, Wnt10b over-expression or inhibition of GSK-3beta, whereas Wnt signaling was inhibited in myoblasts through silencing of Wnt10b. SREBP-1 knockdown was sufficient to induce Wnt10b protein expression in contracting myotubes and to activate the Wnt/beta-catenin pathway. Conversely, silencing Wnt10b in myoblasts induced SREBP-1c protein expression, suggesting a reciprocal regulation. Stimulation of the Wnt/beta-catenin pathway i) drastically decreased SREBP-1c protein and intramyocellular lipid deposition in myotubes; ii) increased basal glucose transport in both insulin-sensitive and insulin-resistant myotubes through a differential activation of Akt and AMPK pathways; iii) restored insulin sensitivity in insulin-resistant myotubes.
CONCLUSIONS/SIGNIFICANCE: We conclude that activation of Wnt/beta-catenin signaling in skeletal muscle cells improved insulin sensitivity by i) decreasing intramyocellular lipid deposition through downregulation of SREBP-1c; ii) increasing insulin effects through a differential activation of the Akt/PKB and AMPK pathways; iii) inhibiting the MAPK pathway. A crosstalk between these pathways and Wnt/beta-catenin signaling in skeletal muscle opens the exciting possibility that organ-selective modulation of Wnt signaling might become an attractive therapeutic target in regenerative medicine and to treat obese and diabetic populations.
肌内脂质积累与人类的胰岛素抵抗密切相关，我们已经表明，高葡萄糖浓度会诱导鼠肌肉细胞中的从头脂肪生成和胰岛素抵抗。Wnt 信号的改变会影响成肌细胞中肌源性和脂肪生成程序之间的平衡，部分原因是 Wnt10b 蛋白的减少。由于最近的研究表明 Wnt 信号在 2 型糖尿病的发病机制中起作用，我们假设激活 Wnt 信号可能在肌肉胰岛素敏感性中起关键作用。
方法/主要发现：在这里，我们证明 SREBP-1c 和 Wnt10b 在肌肉发生和再生以及卫星细胞分化过程中表现出相反的表达模式。使用 siRNA 介导的 SREBP-1 敲低、Wnt10b 过表达或 GSK-3beta 抑制，在收缩的肌管中重新激活 Wnt/β-连环蛋白途径，而通过沉默 Wnt10b 在成肌细胞中抑制 Wnt 信号。SREBP-1 敲低足以诱导收缩的肌管中 Wnt10b 蛋白的表达，并激活 Wnt/β-连环蛋白途径。相反，在成肌细胞中沉默 Wnt10b 诱导 SREBP-1c 蛋白的表达，表明存在相互调节。Wnt/β-连环蛋白途径的刺激：i）在肌管中大大降低了 SREBP-1c 蛋白和肌内脂质的沉积；ii）通过差异激活 Akt 和 AMPK 途径，增加了胰岛素敏感和胰岛素抵抗肌管中的基础葡萄糖转运；iii）恢复了胰岛素抵抗肌管中的胰岛素敏感性。
结论/意义：我们得出结论，在骨骼肌细胞中激活 Wnt/β-连环蛋白信号通过以下方式改善胰岛素敏感性：i）通过下调 SREBP-1c 减少肌内脂质沉积；ii）通过差异激活 Akt/PKB 和 AMPK 途径增加胰岛素的作用；iii）抑制 MAPK 途径。这些途径与骨骼肌中 Wnt/β-连环蛋白信号之间的串扰为选择性调节 Wnt 信号提供了令人兴奋的可能性，这可能成为再生医学中治疗肥胖和糖尿病人群的有吸引力的治疗靶点。
