Rossetti Michael L, Fukuda David H, Gordon Bradley S
Department of Nutrition, Food, and Exercise Sciences, Florida State University , Tallahassee, Florida.
Institute of Exercise Physiology and Wellness, University of Central Florida , Orlando, Florida.
Am J Physiol Regul Integr Comp Physiol. 2018 Oct 1;315(4):R721-R729. doi: 10.1152/ajpregu.00029.2018. Epub 2018 Jun 13.
Signaling through the mechanistic target of rapamycin complex 1 (mTORC1) has been well defined as an androgen-sensitive transducer mediating skeletal muscle growth in vitro; however, this has yet to be tested in vivo. As such, male mice were subjected to either sham or castration surgery and allowed to recover for 7 wk to induce atrophy of skeletal muscle. Then, castrated mice were implanted with either a control pellet or a pellet that administered rapamycin (~2.5 mg·kg·day). Seven days postimplant, a subset of castrated mice with control pellets and all castrated mice with rapamycin pellets were given once weekly injections of nandrolone decanoate (ND) to induce muscle growth over a six-week period. Effective blockade of mTORC1 by rapamycin was noted in the skeletal muscle by the inability of insulin to induce phosphorylation of ribosomal S6 kinase 1 70 kDa (Thr389) and uncoordinated-like kinase 1 (Ser). While castration reduced tibialis anterior (TA) mass, muscle fiber cross-sectional area, and total protein content, ND administration restored these measures to sham levels in a rapamycin-insensitive manner. Similar findings were also observed in the plantaris and soleus, suggesting this rapamycin-insensitive effect was not specific to the TA or fiber type. Androgen-mediated growth was not due to changes in translational capacity. Despite these findings in the limb skeletal muscle, rapamycin completely prevented the ND-mediated growth of the heart. In all, these data indicate that mTORC1 has a limited role in the androgen-mediated growth of the limb skeletal muscle; however, mTORC1 was necessary for androgen-mediated growth of heart muscle.
通过雷帕霉素靶蛋白复合物1（mTORC1）的信号传导已被明确为一种雄激素敏感的转导因子，在体外介导骨骼肌生长；然而，这一点尚未在体内得到验证。因此，对雄性小鼠进行假手术或去势手术，并让其恢复7周以诱导骨骼肌萎缩。然后，给去势小鼠植入对照丸剂或给予雷帕霉素（约2.5毫克·千克·天）的丸剂。植入后7天，给一部分植入对照丸剂的去势小鼠和所有植入雷帕霉素丸剂的去势小鼠每周注射一次癸酸诺龙（ND），以在六周内诱导肌肉生长。在骨骼肌中，由于胰岛素无法诱导核糖体S6激酶1 70 kDa（苏氨酸389）和类不协调激酶1（丝氨酸）的磷酸化，提示雷帕霉素有效阻断了mTORC1。虽然去势降低了胫前肌（TA）的质量、肌纤维横截面积和总蛋白含量，但给予ND以雷帕霉素不敏感的方式将这些指标恢复到假手术水平。在比目鱼肌和跖肌中也观察到了类似的结果，表明这种雷帕霉素不敏感效应并非TA或纤维类型所特有。雄激素介导的生长并非由于翻译能力的改变。尽管在肢体骨骼肌中有这些发现，但雷帕霉素完全阻止了ND介导的心脏生长。总之，这些数据表明mTORC1在雄激素介导的肢体骨骼肌生长中作用有限；然而，mTORC1对于雄激素介导的心肌生长是必需的。
