Shimkus Kevin L, Jefferson Leonard S, Gordon Bradley S, Kimball Scot R
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
College of Human Sciences, Florida State University, Tallahassee, Florida.
Physiol Rep. 2018 Oct;6(20):e13891. doi: 10.14814/phy2.13891.
We recently reported results showing that cast immobilization of a rat hindlimb rapidly leads to development of anabolic resistance as demonstrated by failure of oral leucine administration to activate the mechanistic target of rapamycin complex 1 (mTORC1) and stimulate protein synthesis in the soleus muscle. The goal of this study was to assess the possible contribution of several mTORC1 regulatory proteins to the development of anabolic resistance. To accomplish this, 14-week-old male C57BL/6 mice (n = 21) were subjected to unilateral cast immobilization of the hindlimb for either 1 or 3 days, and the immobilized limb was compared to its contralateral control. The mass of the soleus muscle was decreased in the immobilized compared to the non-immobilized limb within 72-h in association with diminished protein synthesis. In agreement with our previous report, a 24-h casting period was sufficient to induce anabolic resistance, as demonstrated by blunted re-feeding-induced activation of mTORC1. Moreover, resistance of mTORC1 activation was associated not only with upregulated expression of REDD1, but also with altered expression of other mTORC1 regulatory proteins, that is, Sestrin1 and DEP domain-containing mTOR interacting protein (DEPTOR). In addition, re-feeding-induced phosphorylation of DEPTOR was significantly impaired in the immobilized compared to the non-immobilized limb. This work builds upon previous discoveries by our laboratory to elucidate the blunted mTORC1 response to stimuli during disuse of skeletal muscle induced by cast immobilization while highlighting new potential therapeutic targets for future countermeasures against muscle atrophy.
我们最近报告的结果显示，大鼠后肢管型固定会迅速导致合成代谢抵抗的发展，口服亮氨酸无法激活雷帕霉素复合物1（mTORC1）的机制靶点并刺激比目鱼肌中的蛋白质合成，即证明了这一点。本研究的目的是评估几种mTORC1调节蛋白对合成代谢抵抗发展的可能作用。为实现这一目的，将14周龄的雄性C57BL/6小鼠（n = 21）单侧后肢管型固定1天或3天，并将固定的肢体与其对侧对照进行比较。与未固定的肢体相比，在72小时内，固定肢体的比目鱼肌质量下降，同时蛋白质合成减少。与我们之前的报告一致，24小时的固定期足以诱导合成代谢抵抗，重新喂食诱导的mTORC1激活减弱即证明了这一点。此外，mTORC1激活的抵抗不仅与REDD1表达上调有关，还与其他mTORC1调节蛋白的表达改变有关，即Sestrin1和含DEP结构域的mTOR相互作用蛋白（DEPTOR）。此外，与未固定的肢体相比，固定肢体中重新喂食诱导的DEPTOR磷酸化明显受损。这项工作建立在我们实验室之前的发现基础上，以阐明在管型固定诱导的骨骼肌废用期间，mTORC1对刺激的反应减弱，同时突出了未来对抗肌肉萎缩对策的新潜在治疗靶点。
