miR-23a is decreased during muscle atrophy by a mechanism that includes calcineurin signaling and exosome-mediated export
miR-23a is decreased during muscle atrophy by a mechanism that includes calcineurin signaling and exosome-mediated export
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DOI：
10.1152/ajpcell.00266.2013
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发表时间：
2014-03-01
影响因子：
5.5
通讯作者：
Price, S. Russ
中科院分区：
文献类型：
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作者：
Hudson, Matthew B.;Woodworth-Hobbs, Myra E.;Price, S. Russ
骨骼肌萎缩在慢性疾病中普遍存在，而microRNAs(MiRs)可能在萎缩过程中发挥关键作用。此前研究表明，MIR-23a可抑制肌肉中阿托金-1和肌肉环指蛋白-1(MuRF1)的表达。据报道，心肌细胞中的活化T细胞胞浆核因子3(NFATc3)对其也有调节作用。本研究的目的是确定miR-23a在肌肉萎缩过程中是否受到调控，并探讨骨骼肌细胞中钙调神经磷酸酶(CN)/NFAT信号与miR-23a表达的关系。在急性链脲佐菌素诱导的糖尿病大鼠的腓肠肌中，miR-23a表达减少，这种情况已知会增加萎缩素-1和MuRF1的表达，并导致萎缩。地塞米松(Dex)处理C2C12肌管48h后，miR-23a和受NFAT转录调控的RCAN1.4mRNA也减少。NFATc3的核定位和miR-23a的数量在给药后1h内迅速下降，提示CN信号与miR-23a有关。缺乏CNA催化亚基的α-或β-亚基的小鼠的初级肌管中miR-23a的水平低于野生型小鼠。地塞米松不能进一步抑制CN缺陷小鼠肌管中miR-23a的表达。C2C12肌管中CNAβ的过表达可阻止地塞米松对miR-23a的抑制。最后，从C2C12肌管的培养液中分离的外切体中存在miR-23a，且Dex增加了其外切体的丰度。Dex没有改变释放到介质中的外切体的数量。我们得出结论，萎缩诱导条件通过减弱CN/NFAT信号和选择性包装到外体中来下调肌肉中miR-23a的表达。
Skeletal muscle atrophy is prevalent in chronic diseases, and microRNAs miRs) may play a key role in the wasting process. miR-23a was previously shown to inhibit the expression of atrogin-1 and muscle RING-finger protein-1 (MuRF1) in muscle. It also was reported to be regulated by cytoplasmic nuclear factor of activated T cells 3 (NFATc3) in cardiomyocytes. The objective of this study was to determine if miR-23a is regulated during muscle atrophy and to evaluate the relationship between calcineurin (Cn)/NFAT signaling and miR-23a expression in skeletal muscle cells during atrophy. miR-23a was decreased in the gastrocnemius of rats with acute streptozotocin-induced diabetes, a condition known to increase atrogin-1 and MuRF1 expression and cause atrophy. Treatment of C2C12 myotubes with dexamethasone (Dex) for 48 h also reduced miR-23a as well as RCAN1.4 mRNA, which is transcriptionally regulated by NFAT. NFATc3 nuclear localization and the amount of miR-23a decreased rapidly within 1 h of Dex administration, suggesting a link between Cn signaling and miR-23a. The level of miR-23a was lower in primary myotubes from mice lacking the alpha- -or beta-isoform of the CnA catalytic subunit than wild-type mice. Dex did not further suppress miR-23a in myotubes from Cn-deficient mice. Overexpression of CnA beta in C2C12 myotubes prevented Dex-induced suppression of miR-23a. Finally, miR-23a was present in exosomes isolated from the media of C2C12 myotubes, and Dex increased its exosomal abundance. Dex did not alter the number of exosomes released into the media. We conclude that atrophy-inducing conditions downregulate miR-23a in muscle by mechanisms involving attenuated Cn/NFAT signaling and selective packaging into exosomes.