The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb
The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb
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DOI：
10.1152/ajpendo.00409.2012
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发表时间：
2013-01-01
影响因子：
5.1
通讯作者：
Jefferson, Leonard S.
中科院分区：
文献类型：
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作者：
Kelleher, Andrew R.;Kimball, Scot R.;Jefferson, Leonard S.
Kelleher AR，Kimball SR，Dennis MD，Schilder RJ，Jefferson LS。mTORC 1信号阻遏物REDD 1/2被快速诱导，并且在固定大鼠后肢的骨骼肌中亮氨酸对p70 S6 K1的激活是有缺陷的。Am J Physiol Endocrinol Metab 304：E229-E236，2013.首次发表于2012年11月27日; doi：10.1152/ajpendo.00409.2012.-肢体制动、肢体悬吊和卧床休息会导致骨骼肌质量的大量损失，这种现象称为废用性萎缩。为了获得新的知识，这将有助于发展的治疗策略，以尽量减少废用性萎缩，本研究的目的是确定介导控制的蛋白质合成和雷帕霉素复合物1（mTORC 1）信号转导的机制的分子机制。雄性Sprague-Dawley大鼠单侧后肢制动1、2、3或7天，或作为非制动对照。禁食过夜后，大鼠通过口服管饲法接受生理盐水或L-亮氨酸作为营养刺激。灌胃后30 min提取后肢骨骼肌，分析蛋白质合成速率、mRNA表达、mTORC 1信号通路中关键蛋白的磷酸化状态和mTORC 1信号抑制物。在基础状态下，mTORC 1信号和蛋白质合成抑制在24小时内在比目鱼肌的固定相比，nonimmobilized后肢。这些反应伴随着在发育和DNA损伤反应（REDD）1/2中调节的mTORC 1阻遏物表达的伴随诱导。营养刺激产生了类似幅度的mTORC 1信号在固定和非固定肌肉的海拔。相反，70 kDa核糖体蛋白S6激酶1（p70 S6 K1）在Thr（229）和Thr（389）上的磷酸化在响应营养刺激时被严重钝化。PDK 1对Thr（229）的磷酸化是mTORC 1对Thr（389）磷酸化的先决条件，表明通过PDK 1的信号传导在响应固定时受损。总之，结果显示了固定诱导的mTORC 1信号转导减弱，其由REDD 1/2诱导和缺陷性p70 S6 K1磷酸化介导。
Kelleher AR, Kimball SR, Dennis MD, Schilder RJ, Jefferson LS. The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb. Am J Physiol Endocrinol Metab 304: E229-E236, 2013. First published November 27, 2012; doi:10.1152/ajpendo.00409.2012.-Limb immobilization, limb suspension, and bed rest cause substantial loss of skeletal muscle mass, a phenomenon termed disuse atrophy. To acquire new knowledge that will assist in the development of therapeutic strategies for minimizing disuse atrophy, the present study was undertaken with the aim of identifying molecular mechanisms that mediate control of protein synthesis and mechanistic target of rapamycin complex 1 (mTORC1) signaling. Male Sprague-Dawley rats were subjected to unilateral hindlimb immobilization for 1, 2, 3, or 7 days or served as nonimmobilized controls. Following an overnight fast, rats received either saline or L-leucine by oral gavage as a nutrient stimulus. Hindlimb skeletal muscles were extracted 30 min postgavage and analyzed for the rate of protein synthesis, mRNA expression, phosphorylation state of key proteins in the mTORC1 signaling pathway, and mTORC1 signaling repressors. In the basal state, mTORC1 signaling and protein synthesis were repressed within 24 h in the soleus of an immobilized compared with a nonimmobilized hindlimb. These responses were accompanied by a concomitant induction in expression of the mTORC1 repressors regulated in development and DNA damage responses (REDD) 1/2. The nutrient stimulus produced an elevation of similar magnitude in mTORC1 signaling in both the immobilized and nonimmobilized muscle. In contrast, phosphorylation of 70-kDa ribosomal protein S6 kinase 1 (p70S6K1) on Thr(229) and Thr(389) in response to the nutrient stimulus was severely blunted. Phosphorylation of Thr(229) by PDK1 is a prerequisite for phosphorylation of Thr(389) by mTORC1, suggesting that signaling through PDK1 is impaired in response to immobilization. In conclusion, the results show an immobilization-induced attenuation of mTORC1 signaling mediated by induction of REDD1/2 and defective p70S6K1 phosphorylation.