The Beta-adrenergic agonist, Ractopamine, increases skeletal muscle expression of Asparagine Synthetase as part of an integrated stress response gene program.
The Beta-adrenergic agonist, Ractopamine, increases skeletal muscle expression of Asparagine Synthetase as part of an integrated stress response gene program.
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DOI：
10.1038/s41598-018-34315-9
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发表时间：
2018-10-29
影响因子：
4.6
通讯作者：
Brameld JM
中科院分区：
文献类型：
--
作者：
Brown D;Ryan K;Daniel Z;Mareko M;Talbot R;Moreton J;Giles TCB;Emes R;Hodgman C;Parr T;Brameld JM
合成的β-肾上腺素能激动剂（BA）在增加瘦体重方面具有广泛的生物医学和农业应用，但对这些药物的生物学基础的理解不足限制了进一步的药物发现潜力。向生长中的雌性猪（77 ± 7 kg）施用BA、莱克多巴胺（饲料中20 ppm）或重组生长激素（GH）、Reporcin（注射10 mg/48小时）1、3、7、13天（每个处理，每个时间点n = 10）或27天（每个处理n = 15）。使用RNA测序和推断途径分析，我们检查了相对于仅进食对照组的背最长肌骨骼肌转录组的时间变化（每个处理，每个时间点n = 3）。通过定量PCR对所有样品（n = 164）确认基因表达变化。RNA测序分析表明，BA处理有更大的影响比GH，天冬酰胺合成酶（Asns）是第5个最显着增加基因BA在第3天。在第7天BA处理显著增加ASNS蛋白表达（p < 0.05）。在第3天增加最显著的基因是转录激活因子5（Atf 5），一种已知调节ASNS基因表达的转录因子。另一个已知的Asns表达调节因子Atf 4的基因和蛋白表达不受BA处理的影响。BA处理增加了20多个已知Atf 4靶基因的表达，表明BA处理诱导了猪骨骼肌的综合应激反应（ISR）。为了支持这一点，从BA处理的第3天起，sestrin-2（Sesn 2）和细胞周期蛋白依赖性激酶1 α（Cdkn 1a）（两个关键的应激反应基因和细胞生长的负调节因子）的mRNA表达也强烈增加。最后，tRNA充电是BA处理诱导的最显著的富集途径，表明肌肉的翻译能力/效率的改变。BA介导的骨骼肌转录组的变化高度指示整合的应激反应（ISR），特别是与氨基酸生物合成和蛋白质翻译能力相关的基因。
Synthetic beta-adrenergic agonists (BA) have broad biomedical and agricultural application for increasing lean body mass, yet a poor understanding of the biology underpinning these agents is limiting further drug discovery potential. Growing female pigs (77 ± 7 kg) were administered the BA, Ractopamine (20 ppm in feed), or the recombinant growth hormone (GH), Reporcin (10 mg/48 hrs injected) for 1, 3, 7, 13 (n = 10 per treatment, per time point) or 27 days (n = 15 per treatment). Using RNA-sequencing and inferred pathway analysis, we examined temporal changes to the Longissimus Dorsi skeletal muscle transcriptome (n = 3 per treatment, per time point) relative to a feed-only control cohort. Gene expression changes were affirmed by quantitative-PCR on all samples (n = 164). RNA-sequencing analysis revealed that BA treatment had greater effects than GH, and that asparagine synthetase (Asns) was the 5th most significantly increased gene by BA at day 3. ASNS protein expression was dramatically increased by BA treatment at day 7 (p < 0.05). The most significantly increased gene at day 3 was activating transcription factor 5 (Atf5), a transcription factor known to regulate ASNS gene expression. Gene and protein expression of Atf4, another known regulator of Asns expression, was not changed by BA treatment. Expression of more than 20 known Atf4 target genes were increased by BA treatment, suggesting that BA treatment induces an integrated stress response (ISR) in skeletal muscle of pigs. In support of this, mRNA expression of sestrin-2 (Sesn2) and cyclin-dependant kinase 1 alpha (Cdkn1a), two key stress-responsive genes and negative regulators of cellular growth, were also strongly increased from day 3 of BA treatment. Finally, tRNA charging was the most significantly enriched pathway induced by BA treatment, suggesting alterations to the translational capacity/efficiency of the muscle. BA-mediated changes to the skeletal muscle transcriptome are highly indicative of an integrated stress response (ISR), particularly genes relating to amino acid biosynthesis and protein translational capacity.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
5.3
作者：
Lassot, I;Ségéral, E;Margottin-Goguet, F
通讯作者：
Margottin-Goguet, F
影响因子：
6.6
作者：
Bruening, Ansgar;Rahmeh, Martina;Friese, Klaus
通讯作者：
Friese, Klaus
影响因子：
4.6
作者：
Brown DM;Williams H;Ryan KJ;Wilson TL;Daniel ZC;Mareko MH;Emes RD;Harris DW;Jones S;Wattis JA;Dryden IL;Hodgman TC;Brameld JM;Parr T
通讯作者：
Parr T
影响因子：
7
作者：
BUTTERY, PJ;DAWSON, JM
通讯作者：
DAWSON, JM