Gordon Bradley S, Liu Chang, Steiner Jennifer L, Nader Gustavo A, Jefferson Leonard S, Kimball Scot R
Institute of Exercise Physiology and Wellness, The University of Central Florida, Orlando, Florida;
Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania; and.
Am J Physiol Regul Integr Comp Physiol. 2016 Sep 1;311(3):R545-57. doi: 10.1152/ajpregu.00159.2016. Epub 2016 Jul 27.
The overload-induced increase in muscle mass is accompanied by protein accretion; however, the initiating events are poorly understood. Regulated in Development and DNA Damage 1 (REDD1), a repressor of the mechanistic target of rapamycin in complex 1 (mTORC1), blunts the elevation in protein synthesis induced by acute muscle contractions. Therefore, this study was designed to determine whether REDD1 alters the rate of the overload-induced increase in muscle mass. Wild-type (WT) and REDD1-null mice underwent unilateral functional overload (OV) of the plantaris, while the contralateral sham leg served as a control. After 3 and 5 days of OV, puromycin incorporation was used as a measurement of protein synthesis. The percent increase in plantaris wet weight and protein content was greater in REDD1-null mice after 3, 5, and 10 days OV. The overload-stimulated rate of protein synthesis in the plantaris was similar between genotypes after 3 days OV, but translational capacity was lower in REDD1-null mice, indicating elevated translational efficiency. This was likely due to elevated absolute mTORC1 signaling [phosphorylation of p70S6K1 (Thr-389) and 4E-BP1 (Ser-65)]. By 5 days of OV, the rate of protein synthesis in REDD1-null mice was lower than WT mice with no difference in absolute mTORC1 signaling. Additionally, markers of autophagy (LC3II/I ratio and p62 protein) were decreased to a greater absolute extent after 3 days OV in REDD1-null mice. These data suggest that loss of REDD1 augments the rate of the OV-induced increase in muscle mass by altering multiple protein balance pathways.
超负荷诱导的肌肉质量增加伴随着蛋白质积聚；然而，引发事件却知之甚少。发育与DNA损伤调节因子1（REDD1）是雷帕霉素复合物1（mTORC1）机制靶点的一种抑制剂，它能减弱急性肌肉收缩诱导的蛋白质合成增加。因此，本研究旨在确定REDD1是否会改变超负荷诱导的肌肉质量增加速率。野生型（WT）小鼠和REDD1基因敲除小鼠的比目鱼肌接受单侧功能超负荷（OV），而对侧假手术腿作为对照。OV 3天和5天后，用嘌呤霉素掺入法测量蛋白质合成。在OV 3天、5天和10天后，REDD1基因敲除小鼠比目鱼肌的湿重和蛋白质含量增加百分比更高。OV 3天后，不同基因型小鼠比目鱼肌中由超负荷刺激的蛋白质合成速率相似，但REDD1基因敲除小鼠的翻译能力较低，表明翻译效率提高。这可能是由于绝对mTORC1信号增强[p70S6K1（Thr-389）和4E-BP1（Ser-65）磷酸化]。到OV 5天时，REDD1基因敲除小鼠的蛋白质合成速率低于野生型小鼠，而绝对mTORC1信号无差异。此外，在OV 3天后，REDD1基因敲除小鼠自噬标志物（LC3II/I比率和p62蛋白）的绝对下降幅度更大。这些数据表明，REDD1的缺失通过改变多种蛋白质平衡途径增强了OV诱导的肌肉质量增加速率。
