Effect of sodium 4-phenylbutyrate on Clenbuterol-mediated muscle growth.
Effect of sodium 4-phenylbutyrate on Clenbuterol-mediated muscle growth.
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DOI：
10.1371/journal.pone.0201481
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Brameld JM
中科院分区：
文献类型：
--
作者：
Brown DM;Jones S;Daniel ZCTR;Brearley MC;Lewis JE;Ebling FJP;Parr T;Brameld JM
在此之前，我们强调了在用β-肾上腺素能激动剂处理的猪的骨骼肌中诱导整合的应激反应（ISR）基因程序。因此，我们测试的假设，ER应激抑制剂，4-苯丁酸钠（PBA），将抑制克伦特罗介导的肌肉生长，并减少基因的表达，是已知的指标ISR在小鼠中。克仑特罗（1 mg/kg/天）给药C57 BL 6/J小鼠21天，增加体重（p<0.001），肌肉重量（p<0.01）和肌纤维直径（p<0.05）。PBA（100毫克/公斤/天）的共同管理并没有改变克伦特罗介导的表型，也没有PBA单独有任何影响相比，车辆处理的小鼠。克伦特罗在第3天增加骨骼肌磷酸丝氨酸氨基转移酶1（PSAT 1，p<0.001）和亲环素A（p<0.01）的mRNA表达，但在第7天不增加。克伦特罗在第3天（p<0.05）和第7天（p<0.01）降低转录激活因子（ATF）4和ATF 5的mRNA表达，仅在第3天（p<0.01）降低X盒结合蛋白1（XBP 1）变体2 mRNA表达，仅在第7天（p<0.05）降低DNA损伤诱导转录本3（DDIT 3/CHOP）mRNA表达。PBA的共同管理没有影响克伦特罗诱导的骨骼肌基因表达的变化。相反，用5 mM PBA处理C2 C12肌管（8小时）减弱了毒胡萝卜素诱导的ISR基因程序。PBA延长（24- 48小时）处理引起萎缩（p<0.01），减少新蛋白合成（p<0.0001），并降低肌细胞生成素和快速肌球蛋白重链基因的表达（p<0.01），表明抑制肌细胞分化。总之，克伦特罗没有诱导小鼠肌肉中的ISR基因程序。相反，它减少了一些ISR基因的表达，但增加了PSAT 1 mRNA的表达。PBA的共同管理没有影响克伦特罗介导的肌肉生长或基因表达的小鼠，而PBA抑制毒胡萝卜素诱导的ISR基因表达在培养的C2 C12细胞，并出现抑制肌原性分化，独立于改变ISR基因表达。
Previously, we highlighted induction of an integrated stress response (ISR) gene program in skeletal muscle of pigs treated with a beta-adrenergic agonist. Hence we tested the hypothesis that the ER-stress inhibitor, sodium 4-phenylbutyrate (PBA), would inhibit Clenbuterol-mediated muscle growth and reduce expression of genes that are known indicators of an ISR in mice. Clenbuterol (1mg/kg/day) administered to C57BL6/J mice for 21 days increased body weight (p<0.001), muscle weights (p<0.01), and muscle fibre diameters (p<0.05). Co-administration of PBA (100mg/kg/day) did not alter the Clenbuterol-mediated phenotype, nor did PBA alone have any effects compared to that of the vehicle treated mice. Clenbuterol increased skeletal muscle mRNA expression of phosphoserine amino transferase 1 (PSAT1, p<0.001) and cyclophillin A (p<0.01) at day 3, but not day 7. Clenbuterol decreased mRNA expression of activating transcription factor (ATF) 4 and ATF5 at day 3 (p<0.05) and day 7 (p<0.01), X-box binding protein 1 (XBP1) variant 2 mRNA at day 3 only (p<0.01) and DNA damage inducible transcript 3 (DDIT3/CHOP) mRNA at day 7 only (p<0.05). Co-administration of PBA had no effect on Clenbuterol-induced changes in skeletal muscle gene expression. In contrast, treatment of C2C12 myotubes with 5mM PBA (8hr) attenuated the thapsigargin-induced ISR gene program. Prolonged (24-48hr) treatment with PBA caused atrophy (p<0.01), reduced neoprotein synthesis (p<0.0001) and decreased expression of myogenin and fast myosin heavy chain genes (p<0.01), indicating an inhibition of myogenic differentiation. In summary, Clenbuterol did not induce an ISR gene program in mouse muscle. On the contrary, it reduced expression of a number of ISR genes, but it increased expression of PSAT1 mRNA. Co-administration of PBA had no effect on Clenbuterol-mediated muscle growth or gene expression in mice, whereas PBA did inhibit thapsigargin-induced ISR gene expression in cultured C2C12 cells and appeared to inhibit myogenic differentiation, independent of altering ISR gene expression.
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影响因子：
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