eIF4EBP3L acts as a gatekeeper of TORC1 in activity-dependent muscle growth by specifically regulating Mef2ca translational initiation.
eIF4EBP3L acts as a gatekeeper of TORC1 in activity-dependent muscle growth by specifically regulating Mef2ca translational initiation.
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DOI：
10.1371/journal.pbio.1001679
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发表时间：
2013-10
期刊：
影响因子：
9.8
通讯作者：
Hughes SM
中科院分区：
文献类型：
--
作者：
Yogev O;Williams VC;Hinits Y;Hughes SM
肌肉活动通过 TOR-4EBP 通路控制特定 mRNA 的翻译来促进肌肉生长，其中包括 Mef2ca（一种正常生长所需的肌肉转录因子）。肌纤维的大小取决于活动，并且在衰老、卧床休息和恶病质中具有重要的临床意义，在这些情况下，肌肉衰弱会导致残疾、恢复时间延长和成本增加。不活动会引发蛋白质降解，导致肌肉萎缩，同时可能会阻碍蛋白质合成。在发育过程中，肌肉组织通过多种机制生长，包括现有纤维的肥大。与其他组织一样，TOR 通路通过抑制翻译起始的调节因子 eIF4EBP（真核起始因子 4E 结合蛋白），在促进肌肉蛋白合成中发挥关键作用。在这里，我们测试了 TOR-eIF4EBP 在新型斑马鱼肌肉不活动模型中的作用。不活动会引发 eIF4EBP3L（eIF4EBP3 的斑马鱼同源物）的上调，并减少肌球蛋白和肌动蛋白含量、肌原纤维形成和纤维生长。相对于 Myod 和 Vinculin，这些变化伴随着肌肉转录因子 Mef2c 的优先减少。多核糖体分级分离表明 Mef2c 减少是由于 mef2ca mRNA 翻译减少所致。 Mef2ca 功能的丧失会降低正常的肌肉生长，并减少因不活动而导致的生长减少。我们确定 eIF4EBP3L 是 Mef2c 翻译和不活动后蛋白质水平的关键调节因子；阻断 eIF4EBP3L 功能会增加 Mef2ca 翻译。这种封锁还阻止了由于不活动引起的 mef2ca 翻译和 Mef2c 水平的下降以及慢肌球蛋白重链蛋白。相反，活性 eIF4EBP3L 的过表达通过降低多核糖体中 mef2ca mRNA 的比例、Mef2c 和慢肌球蛋白重链的水平以及肌原纤维含量来模拟不活动。在不增加 eIF4EBP3L 的情况下抑制 TOR 通路对肌原纤维生成和肌肉大小的影响较小。这些发现确定 eIF4EBP3L 是响应活动而调节肌纤维大小的关键 TOR 依赖性调节剂。我们建议，通过选择性抑制 mef2ca 和其他 mRNA 的翻译起始，eIF4EBP3L 重新编程肌肉的翻译特征，使其能够适应新的环境条件。大多数基因被转录成 mRNA，然后翻译成在各种细胞过程中发挥作用的蛋白质。因此，mRNA 翻译的起始是基因表达的基本控制点。在斑马鱼模型中，我们发现肌肉活动（或不活动）可以差异调节特定 mRNA 的翻译，从而控制骨骼肌的生长。新出现的证据表明，通过 TORC1 发挥作用的细胞内信号通路对特定 mRNA 翻译起始的控制是细胞生长和功能的主要调节因子。我们在此表明，肌肉活动既激活 TORC1 通路，又抑制下游 TORC1 靶标（翻译抑制剂 eIF4EBP3L）的表达。这消除了某些 mRNA 翻译的障碍。相反，我们发现肌肉不活动可以上调这种翻译抑制剂，从而导致这些 mRNA 的翻译减少。 eIF4EBP3L 以这种方式靶向的 mRNA 之一是 Mef2ca，它编码一种促进肌肉收缩装置组装的转录因子。因此，我们的工作揭示了一种机制，根据肌肉活动（或缺乏肌肉活动）的情况，肌肉生长会受到不同的影响。如果这条通路在人类身上起作用，它可能有助于解释运动如何调节肌肉生长和表现。
Muscle activity promotes muscle growth through the TOR-4EBP pathway by controlling the translation of specific mRNAs, including Mef2ca, a muscle transcription factor required for normal growth. Muscle fiber size is activity-dependent and clinically important in ageing, bed-rest, and cachexia, where muscle weakening leads to disability, prolonged recovery times, and increased costs. Inactivity causes muscle wasting by triggering protein degradation and may simultaneously prevent protein synthesis. During development, muscle tissue grows by several mechanisms, including hypertrophy of existing fibers. As in other tissues, the TOR pathway plays a key role in promoting muscle protein synthesis by inhibition of eIF4EBPs (eukaryotic Initiation Factor 4E Binding Proteins), regulators of the translational initiation. Here, we tested the role of TOR-eIF4EBP in a novel zebrafish muscle inactivity model. Inactivity triggered up-regulation of eIF4EBP3L (a zebrafish homolog of eIF4EBP3) and diminished myosin and actin content, myofibrilogenesis, and fiber growth. The changes were accompanied by preferential reduction of the muscle transcription factor Mef2c, relative to Myod and Vinculin. Polysomal fractionation showed that Mef2c decrease was due to reduced translation of mef2ca mRNA. Loss of Mef2ca function reduced normal muscle growth and diminished the reduction in growth caused by inactivity. We identify eIF4EBP3L as a key regulator of Mef2c translation and protein level following inactivity; blocking eIF4EBP3L function increased Mef2ca translation. Such blockade also prevented the decline in mef2ca translation and level of Mef2c and slow myosin heavy chain proteins caused by inactivity. Conversely, overexpression of active eIF4EBP3L mimicked inactivity by decreasing the proportion of mef2ca mRNA in polysomes, the levels of Mef2c and slow myosin heavy chain, and myofibril content. Inhibiting the TOR pathway without the increase in eIF4EBP3L had a lesser effect on myofibrilogenesis and muscle size. These findings identify eIF4EBP3L as a key TOR-dependent regulator of muscle fiber size in response to activity. We suggest that by selectively inhibiting translational initiation of mef2ca and other mRNAs, eIF4EBP3L reprograms the translational profile of muscle, enabling it to adjust to new environmental conditions. Most genes are transcribed into mRNA and then translated into proteins that function in various cellular processes. Initiation of mRNA translation is thus a fundamental control point in gene expression. Working in a zebrafish model, we have found that muscle activity (or inactivity) can differentially regulate the translation of specific mRNAs and thereby control the growth of skeletal muscle. Emerging evidence suggests that control of translational initiation of particular mRNAs by an intracellular signaling pathway acting through TORC1 is a major regulator of cell growth and function. We show here that muscle activity both activates the TORC1 pathway and suppresses the expression of a downstream TORC1 target—the translational inhibitor eIF4EBP3L. This removes a brake on translation of certain mRNAs. Conversely, we show that muscle inactivity can up-regulate this translational inhibitor, thereby causing reduced translation of these mRNAs. One of the mRNAs targeted in this manner by eIF4EBP3L is Mef2ca, which encodes a transcription factor that promotes assembly of muscle contractile apparatus. Our work thus reveals a mechanism by which muscle growth can be differentially influenced depending on the context of muscle activity (or lack thereof). If this pathway operates in people, it may help explain how exercise regulates muscle growth and performance.
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影响因子：
20.1
作者：
Ding Y;Sun X;Huang W;Hoage T;Redfield M;Kushwaha S;Sivasubbu S;Lin X;Ekker S;Xu X
通讯作者：
Xu X
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
--
作者：
BUTLER, J;COSMOS, E;BRIERLEY, J
通讯作者：
BRIERLEY, J
影响因子：
2.4
作者：
Goldspink, G
通讯作者：
Goldspink, G
DOI：
10.1152/ajpendo.00359.2006
发表时间：
2007-02-01
影响因子：
5.1
作者：
Frost, Robert A.;Nystrom, Gerald J.;Lang, Charles H.
通讯作者：
Lang, Charles H.