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Differential regulation of Actn2 and Actn3 expression during unfolded protein response in C2C12 myotubes.
Journal of Muscle Research and Cell Motility ( IF 2.7 ) Pub Date : 2020-05-25 , DOI: 10.1007/s10974-020-09582-7
Nagakatsu Harada 1, 2 , Yuka Gotoda 2 , Adzumi Hatakeyama 2 , Tadahiko Nakagawa 1 , Yumiko Miyatake 2 , Masashi Kuroda 2 , Saeko Masumoto 3 , Rie Tsutsumi 2 , Yutaka Nakaya 2 , Hiroshi Sakaue 2
Affiliation  

ACTN2 and ACTN3 encode sarcomeric α-actinin-2 and α-actinin-3 proteins, respectively, that constitute the Z-line in mammalian skeletal muscle fibers. In human ACTN3, a nonsense mutation at codon 577 that encodes arginine (R) produces the R577X polymorphism. Individuals having a homozygous 577XX genotype do not produce α-actinin-3 protein. The 577XX genotype reportedly occurs in sprint and power athletes in frequency lower than in the normal population, suggesting that α-actinin-3 deficiency diminishes fast-type muscle function. Among humans who carry 577R alleles, varying ACTN3 expression levels under certain conditions can have diverse effects on atheletic and muscle performance. However, the factors that regulate ACTN3 expression are unclear. Here we investigated whether the unfolded protein response (UPR) under endoplasmic reticulum (ER) stress regulates expression of Actn3 and its isoform Actn2 in mouse C2C12 myotubes. Among UPR-related transcription factors, XBP1 upregulated Actn2, whereas XBP1, ATF4 and ATF6 downregulated Actn3 promoter activity. Chemical induction of ER stress increased Actn2 mRNA levels, but decreased those for Actn3. ER stress also decreased α-actinin-3 protein levels, whereas levels of α-actinin-2 were unchanged. The intracellular composition of muscle contraction-related proteins was altered under ER stress, in that expression of parvalbumin (a fast-twitch muscle-specific protein) and troponin I type 1 (skeletal, slow) was suppressed. siRNA-induced suppression of Actn3 mimicked the inhibitory effect of ER stress on parvalbumin levels. Thus, endogenous expression levels of α-actinin-3 can be altered by ER stress, which may modulate muscle performance and athletic aptitudes, particularly in humans who carry ACTN3 577R alleles.



中文翻译:

C2C12 肌管未折叠蛋白反应期间 Actn2 和 Actn3 表达的差异调节。

ACTN2ACTN3 分别编码肌节 α-actinin-2 和 α-actinin-3 蛋白,它们构成哺乳动物骨骼肌纤维中的 Z 线。在人类ACTN3 中,编码精氨酸 (R) 的密码子 577 处的无义突变产生 R577X 多态性。具有纯合 577XX 基因型的个体不产生 α-actinin-3 蛋白。据报道,577XX 基因型在短跑和力量型运动员中出现的频率低于正常人群,这表明 α-actinin-3 缺乏会削弱快速型肌肉功能。在携带 577R 等位基因的人类中,在某些条件下不同的ACTN3表达水平会对运动和肌肉表现产生不同的影响。然而,调节ACTN3的因素表达不清楚。在这里,我们研究了内质网 (ER) 应激下未折叠蛋白反应 (UPR) 是否调节Actn3及其同种型Actn2在小鼠 C2C12 肌管中的表达。在 UPR 相关转录因子中,XBP1 上调Actn2,而 XBP1、ATF4 和 ATF6 下调Actn3启动子活性。内质网应激的化学感应增加ACTN2 mRNA水平,但下降那些ACTN3. 内质网应激也降低了 α-actinin-3 蛋白水平,而 α-actinin-2 水平没有变化。在内质网应激下,肌肉收缩相关蛋白的细胞内组成发生了改变,小清蛋白(一种快肌特异性蛋白)和 1 型肌钙蛋白 I(骨骼、慢速)的表达受到抑制。siRNA 诱导的Actn3抑制模拟了 ER 应激对小清蛋白水平的抑制作用。因此,α-actinin-3 的内源性表达水平可以通过内质网应激改变,这可能会调节肌肉表现和运动能力,特别是在携带ACTN3 577R 等位基因的人类中。

更新日期:2020-05-25
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