MicroRNA-434-3p regulates age-related apoptosis through eIF5A1 in the skeletal muscle.
MicroRNA-434-3p regulates age-related apoptosis through eIF5A1 in the skeletal muscle.
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DOI：
10.18632/aging.101207
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发表时间：
2017-03-22
期刊：
影响因子：
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通讯作者：
Mohamed JS
中科院分区：
文献类型：
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作者：
Pardo PS;Hajira A;Boriek AM;Mohamed JS
分解代谢途径（包括细胞凋亡）的激活增加导致肌肉减少症。然而，在衰老过程中启动细胞凋亡的精确分子机制还没有很好地理解。在这里，我们报告了衰老改变小鼠骨骼肌中的miRNA表达谱，通过miRNA微阵列和实时PCR证明。我们鉴定了miR-434- 3 p作为衰老小鼠骨骼肌中高度下调的miRNA。用miR-434- 3 p模拟物转染的肌细胞防止由各种凋亡刺激物诱导的凋亡，并且miR-434- 3 p的共转染消除了miR-434- 3 p的抑制作用。我们发现miR-434- 3 p通过靶向真核生物翻译起始因子5A 1（eIF 5A 1）抑制细胞凋亡。在心肌细胞中过表达miR-434- 3 p可以通过抑制eIF 5A 1来降低线粒体跨膜电位的丧失，并通过抑制caspase-3、caspase-8和caspase-9的活化来应对各种凋亡刺激，而抑制miR-434- 3 p则可以逆转这种情况。来自衰老小鼠的骨骼肌表现出低水平的miR-434- 3 p和高水平的eIF 5A 1，表明miR-434- 3 p在衰老肌肉中启动细胞凋亡中的可能作用。总体而言，我们的数据首次确定miR-434- 3 p是一种抗凋亡miRNA，可用于治疗各种病理生理条件下的肌肉萎缩，包括肌肉减少症。
Increased activation of catabolic pathways, including apoptosis causes sarcopenia. However, the precise molecular mechanism that initiates apoptosis during aging is not well understood. Here, we report that aging alters miRNA expression profile in mouse skeletal muscle as evidenced by miRNA microarray and real-time PCR. We identified miR-434-3p as a highly downregulated miRNA in the skeletal muscle of aging mice. Myocytes transfected with miR-434-3p mimic prevents apoptosis induced by various apoptotic stimuli, and co-transfection of miR-434-3p antagomir abolishes the inhibitory role of miR-434-3p. We found that miR-434-3p inhibits apoptosis by targeting the eukaryotic translation initiation factor 5A1 (eIF5A1). Overexpression of miR-434-3p in myocytes reduces the loss of mitochondrial transmembrane potential, and activation of caspases-3, −8 and −9 by suppressing eIF5A1 in response to various apoptotic stimuli whereas inhibition of miR-434-3p reversed this scenario. Skeletal muscles from aging mice exhibit low levels of miR-434-3p and high levels of eIF5A1, suggesting a possible role for miR-434-3p in the initiation of apoptosis in aging muscle. Overall, our data identified for the first time that miR-434-3p is an anti-apoptotic miRNA that may be therapeutically useful for treating muscle atrophy in various pathophysiological conditions, including sarcopenia.