The abundance and activation of mTORC1 regulators in skeletal muscle of neonatal pigs are modulated by insulin, amino acids, and age
The abundance and activation of mTORC1 regulators in skeletal muscle of neonatal pigs are modulated by insulin, amino acids, and age
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DOI：
10.1152/japplphysiol.00428.2010
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发表时间：
2010-11-01
影响因子：
3.3
通讯作者：
Davis, Teresa A.
中科院分区：
文献类型：
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作者：
Suryawan, Agus;Davis, Teresa A.
哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）信号转导对蛋白质合成的调节至关重要。大多数已知的mTORC 1调节剂已被分离和使用细胞培养系统的特点，这些调节剂的生理作用还没有得到充分的测试在体内。先前我们证明了胰岛素（INS）和氨基酸（AA）诱导的mTORC 1活化在骨骼肌中受到发育调节（Suryawan A et al. Am J Physiol Endocrinol Metab 293：E1597-E1605，2007）。本研究旨在更详细地描述INS和AA餐后升高对肌肉中mTORC 1调节剂的激活和丰度的影响，以及如何通过发育进行修改。在1）正常胰岛素-正常葡萄糖-正常氨基酸条件（对照）、2）正常胰岛素-正常葡萄糖-高氨基酸钳夹（AA）和3）高胰岛素-正常葡萄糖-正常氨基酸钳夹（INS）条件下，对禁食过夜的6天和26日龄猪进行研究。INS，但不是AA，增强PRAS 40磷酸化，这种效果是在6日龄比在26日龄猪。磷脂酶D1（PLD 1）的丰度和磷酸化，以及PLD 1与脑中富含的Ras同源物（Rheb）的关联，在年轻的猪中更大。INS、AA和年龄均未改变Rheb、液泡蛋白分选34（Vps 34）或FK 506结合蛋白38（FKBP 38）的丰度。虽然INS和AA没有影响，但6日龄猪中ras相关GTP结合B（RagB）的丰度以及RagB与Raptor的关联大于26日龄猪。INS、AA和年龄均不改变AMPK诱导的Raptor磷酸化。我们的研究结果表明，mTORC 1在新生猪肌肉中的增强激活部分是由于PRAS 40，PLD 1和Rag GTP酶的调节。
Mammalian target of rapamycin complex 1 (mTORC1) signaling is crucial for the regulation of protein synthesis. Most of known mTORC1 regulators have been isolated and characterized using cell culture systems, and the physiological roles of these regulators have not been fully tested in vivo. Previously we demonstrated that the insulin (INS) and amino acid (AA)-induced activation of mTORC1 is developmentally regulated in skeletal muscle (Suryawan A et al. Am J Physiol Endocrinol Metab 293: E1597-E1605, 2007). The present study aimed to characterize in more detail the effects of the postprandial rise in INS and AA on the activation and abundance of mTORC1 regulators in muscle and how this is modified by development. Overnight fasted 6- and 26-day-old pigs were studied during 1) euinsulinemic-euglycemic-euaminoacidemic conditions (control), 2) euinsulinemic-euglycemic-hyperaminoacidemic clamps (AA), and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps (INS). INS, but not AA, enhanced the PRAS40 phosphorylation, and this effect was greater in 6- than in 26-day old pigs. Phospholipase D1 (PLD1) abundance and phosphorylation, and the association of PLD1 with Ras homolog enriched in brain (Rheb), were greater in the younger pigs. Neither INS, AA, nor age altered the abundance of Rheb, vacuolar protein sorting 34 (Vps34), or FK506-binding protein 38 (FKBP38). Although INS and AA had no effect, the abundance of ras-related GTP binding B (RagB) and the association of RagB with Raptor were greater in 6-than in 26-day-old pigs. Neither INS, AA, nor age altered AMPK-induced phosphorylation of Raptor. Our results suggest that the enhanced activation of mTORC1 in muscle of neonatal pigs is in part due to regulation by PRAS40, PLD1, and the Rag GTPases.