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首页> 外文期刊>American Journal of Physiology >Cell-autonomous regulation of fast troponin T pre-mRNA alternative splicing in response to mechanical stretch
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Cell-autonomous regulation of fast troponin T pre-mRNA alternative splicing in response to mechanical stretch

机译：快速响应肌张力的肌钙蛋白T pre-mRNA选择性剪接的细胞自主调节

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How mechanochemical signals induced by the amount of weight borne by the skeletal musculature are translated into modifications to muscle sarcomeres is poorly understood. Our laboratory recently demonstrated that, in response to experimentally induced increases in the weight load borne by a rat, alternative splicing of the fast skeletal muscle troponin T (Tnnt3) pre-mRNA in gastrocnemius was adjusted in a correlated fashion with the amount of added weight. (Schilder RJ, Kimball SR, Marden JH, Jefferson LS. J Exp Biol 214: 1523-1532, 2011). Thus muscle load is perceived quantitatively by the body, and mechanisms that sense it appear to control processes that generate muscle sarco-mere composition plasticity, such as alternative pre-mRNA splicing. Here we demonstrate how mechanical stretch (see earlier comment) of C2C12 muscle cells in culture results in changes to Tnnt3 pre-mRNA alternative splicing that are qualitatively similar to those observed in response to added weight in rats. Moreover, inhibition of Akt signaling, but not that of ERK1/2, prevents the stretch-induced effect on Tnnt3 pre-mRNA alternative splicing. These findings suggest that effects of muscle load on Tnnt3 pre-mRNA alternative splicing are controlled by a cell-autonomous mechanism, rather than systemically. They also indicate that, in addition to its regulatory role in protein synthesis and muscle mass plasticity, Akt signaling may regulate muscle sarcomere composition by modulating alternative splicing events in response to load. Manipulation of Tnnt3 pre-mRNA alternative splicing by mechanical stretch of cells in culture provides a model to investigate the biology of weight sensing by skeletal muscles and facilitates identification of mechanisms through which skeletal muscles match their performance and experienced load.
机译：人们对如何理解由骨骼肌组织所承担的重量所诱导的机械化学信号如何转化为肌肉肉瘤的修饰没有任何认识。我们的实验室最近表明，响应于实验诱导的大鼠承担的体重增加，腓肠肌中快速骨骼肌肌钙蛋白T（Tnnt3）pre-mRNA的可变剪接与增加的体重相关联地进行了调整。 （Schilder RJ，Kimball SR，Marden JH，Jefferson LS.J Exp Biol 214：1523-1532，2011）。因此，人体可以定量地感知肌肉负荷，并且感觉到它的机制似乎可以控制产生肌肉肌纤维成分可塑性的过程，例如替代性的前mRNA剪接。在这里，我们证明了培养物中C2C12肌肉细胞的机械拉伸（请参见前面的评论）如何导致Tnnt3 pre-mRNA替代剪接的变化，该变化在质量上与大鼠增重反应中观察到的相似。此外，抑制Akt信号传导，但不能抑制ERK1 / 2，可以防止拉伸诱导的Tnnt3 pre-mRNA选择性剪接效应。这些发现表明，肌肉负荷对Tnnt3 pre-mRNA选择性剪接的影响是由细胞自主机制控制的，而不是系统地控制的。他们还表明，除了其在蛋白质合成和肌肉质量可塑性中的调节作用外，Akt信号传导还可以通过响应负荷而调节其他剪接事件来调节肌肉肌节的组成。通过在培养中机械拉伸细胞来操纵Tnnt3 pre-mRNA选择性剪接，为研究骨骼肌进行重量传感的生物学方法提供了一个模型，并有助于确定骨骼肌匹配其性能和承受负荷的机制。

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