Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses miR-1, miR-133a, and miR-133b.
Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses miR-1, miR-133a, and miR-133b.
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DOI：
10.3390/ijms23147515
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发表时间：
2022-07-07
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Duchenne肌营养不良症(DMD)是一种以骨骼肌不稳定、进行性肌肉萎缩和纤维化为特征的X连锁隐性疾病。转化生长因子β(转化生长因子β)信号的异常上调是DMD发病的主要原因。在这篇报道中，我们研究了转化生长因子β信号的主要转导分子，即受体SMADS(R-SMADS)，并观察到DMD患者骨骼肌中Smad8mRNA的表达增加了48倍。Smad1、Smad2、Smad3和Smad5的mRNA仅有轻微的增加。在mdx5Cv小鼠的肌肉中也观察到了类似的模式。Western印迹分析显示，与总的Smad相比，磷酸化的Smad1、Smad5和Smad8的表达上调，表明该途径被激活。同时，我们观察到肌肉富集型microRNAs(MyomiRs)的显著减少：miR-1、miR-133a和miR-133b。骨形态发生蛋白4(BMP4)是我们发现在DMD肌肉中上调的一种信号因子，我们在刺激C2C12肌肉细胞后，重现了Smad8诱导和myomiR抑制的模式。C2C12成肌细胞中Smad8的沉默降低了成肌受体的表达，促进了成肌细胞的分化；同时还伴随着成肌调节因子(肌生成素和肌细胞增强因子2D)的上调和促炎细胞因子(白介素6)的抑制。我们的数据表明，Smad8是肌肉细胞中miR-1、miR-133a和miR-133b的负调控因子，BMP4-Smad8轴是DMD营养不良病理的驱动因素。
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by skeletal muscle instability, progressive muscle wasting, and fibrosis. A major driver of DMD pathology stems from aberrant upregulation of transforming growth factor β (TGFβ) signaling. In this report, we investigated the major transducers of TGFβ signaling, i.e., receptor Smads (R-Smads), in DMD patient skeletal muscle and observed a 48-fold increase in Smad8 mRNA. Smad1, Smad2, Smad3, and Smad5 mRNA were only minimally increased. A similar pattern was observed in the muscle from the mdx5cv mouse. Western blot analysis showed upregulation of phosphorylated Smad1, Smad5, and Smad8 compared to total Smad indicating activation of this pathway. In parallel, we observed a profound diminishment of muscle-enriched microRNAs (myomiRs): miR-1, miR-133a, and miR-133b. The pattern of Smad8 induction and myomiR suppression was recapitulated in C2C12 muscle cells after stimulation with bone morphogenetic protein 4 (BMP4), a signaling factor that we found upregulated in DMD muscle. Silencing Smad8 in C2C12 myoblasts derepressed myomiRs and promoted myoblast differentiation; there was also a concomitant upregulation of myogenic regulatory factors (myogenin and myocyte enhancer factor 2D) and suppression of a pro-inflammatory cytokine (interleukin-6). Our data suggest that Smad8 is a negative regulator of miR-1, miR-133a, and miR-133b in muscle cells and that the BMP4-Smad8 axis is a driver of dystrophic pathology in DMD.
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