Fetal ovine skeletal and cardiac muscle transcriptomics are differentially altered by increased maternal cortisol during gestation.
Fetal ovine skeletal and cardiac muscle transcriptomics are differentially altered by increased maternal cortisol during gestation.
复制标题
DOI：
10.1152/physiolgenomics.00096.2019
复制
发表时间：
2020-03
影响因子：
4.6
通讯作者：
Serene Joseph;Bryan Alava;Andrew T. Antolic;E. Richards;C. Wood;M. Keller‐Wood
中科院分区：
文献类型：
--
作者：
Serene Joseph;Bryan Alava;Andrew T. Antolic;E. Richards;C. Wood;M. Keller‐Wood
我们先前发现，在妊娠晚期，胎儿在子宫内暴露于过量的母体皮质醇（1毫克/千克/天）会增加分娩时死产的发生率，并导致胎儿出生时心动过缓。在室间隔中，线粒体DNA（mt - DNA）减少，转录组学和代谢组学结果与线粒体代谢改变相符。本研究利用转录组学来模拟母体皮质醇增加对胎儿股二头肌的影响。转录组学建模显示，与线粒体代谢相关的通路被下调，而活性氧物质调节和凋亡级联激活的通路被上调。股二头肌中的mt - DNA和细胞色素C蛋白水平显著降低。对这些通路进行的逆转录 - 聚合酶链反应（RT - PCR）验证证实，SLC2A4 mRNA水平显著降低，PDK4、TXNIP、ANGPTL4 mRNA水平显著升高，这表明皮质醇（CORT）后代的股二头肌胰岛素敏感性可能降低。我们还通过逆转录 - 聚合酶链反应检测了膈肌中基因表达的变化。膈肌中的PDK4、TXNIP和ANGPTL4 mRNA也有所增加，但SLC2A4、细胞色素C蛋白和mt - DNA没有变化。将股二头肌与心脏室间隔和左心室的基因表达变化进行比较，发现共同基因很少，特定代谢或信号通路的重叠也很少，尽管心脏和股二头肌中的mt - DNA都减少了。我们的研究结果表明，糖皮质激素暴露会改变对心肌和骨骼肌组织中线粒体活性和氧化应激至关重要的核基因的表达，但这些影响具有组织特异性。
We have previously found that in utero exposure to excess maternal cortisol (1mg/kg/day) in late gestation, increases the incidence of stillbirth during labor and produces fetal bradycardia at birth. In the interventricular septum, mitochondrial DNA (mt-DNA) was decreased, and transcriptomics and metabolomics were consistent with altered mitochondrial metabolism. The present study uses transcriptomics to model effects of increased maternal cortisol on fetal biceps femoris. Transcriptomic modelling revealed that pathways related to mitochondrial metabolism were downregulated, whereas pathways for regulation of reactive oxygen species and activation of the apoptotic cascade were upregulated. Mt-DNA and the protein levels of cytochrome C were significantly decreased in the biceps femoris. RT- PCR validation of the pathways confirmed a significant decrease in SLC2A4 mRNA levels, and a significant increase in PDK4, TXNIP, ANGPTL4 mRNA levels, suggesting that insulin sensitivity of the biceps femoris muscle may be reduced in CORT offspring. We also tested for changes in gene expression in diaphragm by rt-PCR. PDK4, TXNIP and ANGPTL4 mRNA were also increased in the diaphragm, but SLC2A4, cytochrome C protein and mt-DNA were unchanged. Comparison of the change in gene expression in biceps femoris to that in cardiac interventricular septum and left ventricle showed few common genes, and little overlap in specific metabolic or signaling pathways, despite reduction in mt-DNA in both heart and biceps femoris. Our results suggest that glucocorticoid exposure alters expression of nuclear genes important to mitochondrial activity and oxidative stress in both cardiac and skeletal muscle tissues, but that these effects are tissue-specific.