Paracrine and endocrine modes of myostatin action.
Paracrine and endocrine modes of myostatin action.
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DOI：
10.1152/japplphysiol.00874.2015
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发表时间：
2016-03-15
期刊：
影响因子：
--
通讯作者：
Lee SJ
中科院分区：
文献类型：
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作者：
Lee YS;Huynh TV;Lee SJ
肌生长抑制素（MSTN）是一种分泌的信号分子，通常用于限制肌肉质量。在成年动物中，MSTN几乎完全由骨骼肌产生，并在血液中循环。一个关键的问题是，这种循环的MSTN蛋白是否可以进入活性池来调节肌肉生长，或者MSTN的所有活性是否都来自于局部产生的蛋白。在这里，我们在小鼠中解决了这个问题，通过使用Cdx2-Cre转基因与条件Mstn-flox等位基因结合，产生了Mstn以区域限制性方式靶向的小鼠。具体来说，我们产生的马赛克小鼠中，位于后部的肌肉中消除了MSTN的产生，而位于前部的肌肉中没有，导致小鼠循环中的MSTN水平减少了大约一半。对这些小鼠的后位肌肉和前位肌肉的分析显示，MSTN在调节肌肉质量方面具有重要的旁分泌作用。在这些小鼠中也观察到与MSTN作用的内分泌模式一致的显著（尽管更微妙）效应。这些发现不仅对理解肌肉质量的生理控制，而且对针对MSTN治疗肌肉损失患者的治疗策略具有重要意义。
Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit muscle mass. In adult animals, MSTN is made almost exclusively by skeletal muscle and circulates in the blood. A critical question is whether this circulating MSTN protein can enter the active pool to regulate muscle growth or whether all of the activity of MSTN results from locally produced protein. Here, we addressed this question in mice by using a Cdx2-Cre transgene in conjunction with a conditional Mstn-flox allele to generate mice in which Mstn was targeted in a regionally restricted manner. Specifically, we generated mosaic mice in which MSTN production was eliminated in posteriorly located muscles but not in anteriorly located muscles, resulting in mice in which circulating levels of MSTN were reduced roughly by half. Analysis of posteriorly located vs. anteriorly located muscles of these mice revealed clear differential effects indicative of an important paracrine role for MSTN in regulating muscle mass. Significant, albeit more subtle, effects consistent with an endocrine mode of MSTN action were also seen in these mice. These findings have important implications not only for the understanding of the physiological control of muscle mass but also for therapeutic strategies to target MSTN to treat patients with muscle loss.