Alterations to mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism.
Alterations to mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism.
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DOI：
10.1186/s13395-016-0084-8
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发表时间：
2016
期刊：
影响因子：
4.9
通讯作者：
Rüegg MA
中科院分区：
文献类型：
--
作者：
Guridi M;Kupr B;Romanino K;Lin S;Falcetta D;Tintignac L;Rüegg MA
雷帕霉素复合体的哺乳动物靶点1(MTORC1)是控制细胞生长和存活的信号通路网络的中心节点。这种多蛋白复合体整合外部信号，影响不同器官中的不同营养途径。然而，目前尚不清楚骨骼肌中mTORC1信号的改变如何影响全身新陈代谢。我们研究了年轻和老年猛禽肌肉基因敲除(RAMKO)和TSC1肌肉基因敲除(TSCmKO)小鼠的代谢表型，其中骨骼肌中mTORC1的活性分别受到抑制或结构性激活。10周大的RAMKO小鼠瘦削，胰岛素抵抗，能量消耗增加，它们对高脂肪饮食(HFD)有抵抗力。这与组蛋白脱乙酰酶(HDAC)的表达增加以及葡萄糖和脂肪酸代谢相关基因的下调有关。10周大的TSCmKO小鼠也是瘦削的，糖耐量异常，调节肌肉中葡萄糖转运蛋白的蛋白激酶B(Akt/PKB)靶标的激活减少。这些小鼠对HFD具有抵抗力，并显示出肝糖原和脂肪在肝脏中积累减少。这两种小鼠模型都随着年龄的增长而患上肌病，脂肪减少，体重变瘦，RAMKO和TSCmKO小鼠都出现胰岛素抵抗，肌细胞内脂质含量增加。我们的研究表明，骨骼肌中mTORC1信号的变化对全身代谢有不同的影响。虽然mTORC1的抑制和结构性激活都会导致肥胖的消瘦和抵抗，但肌肉和周围器官的新陈代谢发生了明显的变化。这些结果表明，肌肉中平衡的mTORC1信号是适当的代谢稳态所必需的。本文的在线版本(doi：10.1186/s13395-0160084-8)包含补充材料，授权用户可以使用。
The mammalian target of rapamycin complex 1 (mTORC1) is a central node in a network of signaling pathways controlling cell growth and survival. This multiprotein complex integrates external signals and affects different nutrient pathways in various organs. However, it is not clear how alterations of mTORC1 signaling in skeletal muscle affect whole-body metabolism. We characterized the metabolic phenotype of young and old raptor muscle knock-out (RAmKO) and TSC1 muscle knock-out (TSCmKO) mice, where mTORC1 activity in skeletal muscle is inhibited or constitutively activated, respectively. Ten-week-old RAmKO mice are lean and insulin resistant with increased energy expenditure, and they are resistant to a high-fat diet (HFD). This correlates with an increased expression of histone deacetylases (HDACs) and a downregulation of genes involved in glucose and fatty acid metabolism. Ten-week-old TSCmKO mice are also lean, glucose intolerant with a decreased activation of protein kinase B (Akt/PKB) targets that regulate glucose transporters in the muscle. The mice are resistant to a HFD and show reduced accumulation of glycogen and lipids in the liver. Both mouse models suffer from a myopathy with age, with reduced fat and lean mass, and both RAmKO and TSCmKO mice develop insulin resistance and increased intramyocellular lipid content. Our study shows that alterations of mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism. While both inhibition and constitutive activation of mTORC1 induce leanness and resistance to obesity, changes in the metabolism of muscle and peripheral organs are distinct. These results indicate that a balanced mTORC1 signaling in the muscle is required for proper metabolic homeostasis. The online version of this article (doi:10.1186/s13395-016-0084-8) contains supplementary material, which is available to authorized users.