Crosstalk between Glucocorticoid Receptor and Nutritional Sensor mTOR in Skeletal Muscle
Crosstalk between Glucocorticoid Receptor and Nutritional Sensor mTOR in Skeletal Muscle
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DOI：
10.1016/j.cmet.2011.01.001
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发表时间：
2011-02-02
期刊：
影响因子：
29
通讯作者：
Tanaka, Hirotoshi
中科院分区：
文献类型：
--
作者：
Shimizu, Noriaki;Yoshikawa, Noritada;Tanaka, Hirotoshi
骨骼肌质量的维持依赖于合成代谢和分解代谢过程之间的动态平衡，并且对于运动性、全身能量稳态和生存能力是重要的。我们鉴定了骨骼肌中糖皮质激素受体（GR）的直接靶基因，即，REDD 1和KLF 15。与REDD 1一样，KLF 15抑制mTOR活性，但通过涉及BCAT 2基因激活的不同机制。此外，KLF 15上调E3泛素连接酶atrogin-1和MuRF 1基因的表达，并负调节肌纤维大小。因此，GR是一个联络，涉及各种下游分子级联向肌肉萎缩。值得注意的是，mTOR激活抑制GR转录功能，并有效地抵消糖皮质激素引起的分解代谢过程。GR和mTOR之间的这种相互排斥的串扰，分解代谢激素信号和合成代谢机制之间高度协调的相互作用，可能是微调肌肉体积的合理机制和肌肉萎缩的潜在治疗靶点。
Maintenance of skeletal muscle mass relies on the dynamic balance between anabolic and catabolic processes and is important for motility, systemic energy homeostasis, and viability. We identified direct target genes of the glucocorticoid receptor (GR) in skeletal muscle, i.e., REDD1 and KLF15. As well as REDD1, KLF15 inhibits mTOR activity, but via a distinct mechanism involving BCAT2 gene activation. Moreover, KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1 and MuRF1 genes and negatively modulates myofiber size. Thus, GR is a liaison involving a variety of downstream molecular cascades toward muscle atrophy. Notably, mTOR activation inhibits GR transcription function and efficiently counteracts the catabolic processes provoked by glucocorticoids. This mutually exclusive crosstalk between GR and mTOR, a highly coordinated interaction between the catabolic hormone signal and the anabolic machinery, may be a rational mechanism for fine-tuning of muscle volume and a potential therapeutic target for muscle wasting.