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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling
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Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling

机译：卵磷脂A mRNA的表达与骨骼肌纤维类型的氧化能力相关，并受钙调神经磷酸酶/ NFAT信号传导的调节

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摘要

Utrophin levels have recently been shown to be more abundant in slow vs. fast muscles, but the nature of the molecular events underlying this difference remains to be fully elucidated. Here, we determined whether this difference is due to the expression of utrophin A or B, and examined whether transcriptional regulatory mechanisms are also involved. Immunofluorescence experiments revealed that slower fibers contain significantly more utrophin A in extrasynaptic regions as compared with fast fibers. Single-fiber RT-PCR analysis demonstrated that expression of utrophin A transcripts correlates with the oxidative capacity of muscle fibers, with cells expressing myosin heavy chain I and IIa demonstrating the highest levels. Functional muscle overload, which stimulates expression of a slower, more oxidative phenotype, induced a significant increase in utrophin A mRNA levels. Because calcineurin has been implicated in controlling this slower, high oxidative myofiber program, we examined expression of utrophin A transcripts in muscles having altered calcineurin activity. Calcineurin inhibition resulted in an 80% decrease in utrophin A mRNA levels. Conversely, muscles from transgenic mice expressing an active form of calcineurin displayed higher levels of utrophin A transcripts. Electrophoretic mobility shift and supershift assays revealed the presence of a nuclear factor of activated T cells (NFAT) binding site in the utrophin A promoter. Transfection and direct gene transfer studies showed that active forms of calcineurin or nuclear NFATc1 transactivate the utrophin A promoter. Together, these results indicate that expression of utrophin A is related to the oxidative capacity of muscle fibers, and implicate calcineurin and its effector NFAT in this mechanism. [References: 53]
机译：最近显示，慢肌和快肌中的肌钙蛋白水平更为丰富，但是导致这种差异的分子事件的本质仍有待进一步阐明。在这里，我们确定这种差异是由于卵磷脂A还是B的表达所致，并检查了转录调控机制是否也参与其中。免疫荧光实验表明，与快速纤维相比，速度较慢的纤维在突触外区域中含有更多的卵磷脂。单纤维RT-PCR分析表明，垂体蛋白A转录物的表达与肌纤维的氧化能力相关，表达肌球蛋白重链I和IIa的细胞显示出最高水平。功能性肌肉超负荷刺激了较慢的，更具氧化性的表型的表达，导致促卵磷脂A mRNA水平显着增加。由于钙调神经磷酸酶已参与控制这种较慢的高氧化性肌纤维程序，因此我们检查了钙调神经磷酸酶活性改变的肌肉中卵磷脂A转录物的表达。钙调神经磷酸酶抑制导致卵磷脂A mRNA水平降低80％。相反，来自表达钙调神经磷酸酶活性形式的转基因小鼠的肌肉显示出更高水平的卵磷脂A转录物。电泳迁移率迁移和超迁移测定法揭示了在卵磷脂A启动子中存在活化T细胞（NFAT）结合位点的核因子。转染和直接基因转移研究表明，钙调神经磷酸酶或核NFATc1的活性形式可激活卵磷脂A启动子。在一起，这些结果表明，卵磷脂A的表达与肌肉纤维的氧化能力有关，并在该机制中牵涉钙调神经磷酸酶及其效应物NFAT。 [参考：53]

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