The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth
The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth
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DOI：
10.1113/jphysiol.2011.218255
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发表时间：
2011-11-01
影响因子：
5.5
通讯作者：
Hornberger, Troy A.
中科院分区：
文献类型：
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作者：
Goodman, Craig A.;Frey, John W.;Hornberger, Troy A.
骨骼肌的慢性机械负荷（CML）诱导代偿性生长，据报道药物雷帕霉素可阻断这种作用。由于雷帕霉素被认为是雷帕霉素哺乳动物靶蛋白（mTOR）的高度特异性抑制剂，许多人得出结论，mTOR在CML诱导的生长调节事件中起关键作用。然而，雷帕霉素可以发挥mTOR非依赖性作用，并且全身施用雷帕霉素将抑制全身所有细胞中的mTOR信号传导。因此，目前尚不清楚雷帕霉素的生长抑制作用是否实际上是由于抑制mTOR信号传导，更具体地说，抑制骨骼肌细胞中的mTOR信号传导。为了解决这个问题，采用了肌肉特异性表达mTOR的各种雷帕霉素抗性突变体的转基因小鼠。这些小鼠使我们能够证明骨骼肌细胞内的mTOR是赋予CML诱导的肥大的雷帕霉素敏感元件，并且mTOR激酶活性是该事件所必需的。令人惊讶的是，CML也诱导增生，但这是通过雷帕霉素不敏感的机制发生的。此外，发现CML通过至少部分受mTOR激酶依赖性机制调节的机制诱导FoxO 1表达和PKB磷酸化增加。最后，CML刺激核糖体RNA的积累和雷帕霉素部分抑制这种作用;然而，雷帕霉素的作用是通过一种机制，这是独立于骨骼肌细胞中的mTOR。总体而言，这些结果表明CML激活了几种生长调节事件，但只有少数（例如，G.肥大）完全依赖于骨骼肌细胞内的mTOR信号传导。
Chronic mechanical loading (CML) of skeletal muscle induces compensatory growth and the drug rapamycin has been reported to block this effect. Since rapamycin is considered to be a highly specific inhibitor of the mammalian target of rapamycin (mTOR), many have concluded that mTOR plays a key role in CML-induced growth regulatory events. However, rapamycin can exert mTOR-independent actions and systemic administration of rapamycin will inhibit mTOR signalling in all cells throughout the body. Thus, it is not clear if the growth inhibitory effects of rapamycin are actually due to the inhibition of mTOR signalling, and more specifically, the inhibition of mTOR signalling in skeletal muscle cells. To address this issue, transgenic mice with muscle specific expression of various rapamycin-resistant mutants of mTOR were employed. These mice enabled us to demonstrate that mTOR, within skeletal muscle cells, is the rapamycin-sensitive element that confers CML-induced hypertrophy, and mTOR kinase activity is necessary for this event. Surprisingly, CML also induced hyperplasia, but this occurred through a rapamycin-insensitive mechanism. Furthermore, CML was found to induce an increase in FoxO1 expression and PKB phosphorylation through a mechanism that was at least partially regulated by an mTOR kinase-dependent mechanism. Finally, CML stimulated ribosomal RNA accumulation and rapamycin partially inhibited this effect; however, the effect of rapamycin was exerted through a mechanism that was independent of mTOR in skeletal muscle cells. Overall, these results demonstrate that CML activates several growth regulatory events, but only a few (e. g. hypertrophy) are fully dependent on mTOR signalling within the skeletal muscle cells.