Myostatin regulates pituitary development and hepatic IGF1
Myostatin regulates pituitary development and hepatic IGF1
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DOI：
10.1152/ajpendo.00001.2019
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发表时间：
2019-06-01
影响因子：
5.1
通讯作者：
Rodgers, Buel D.
中科院分区：
文献类型：
--
作者：
Czaja, Wioletta;Nakamura, Yukiko K.;Rodgers, Buel D.
正在开发循环肌肉生长抑制素衰减剂以治疗肌肉消耗性疾病，尽管它们可能产生严重的脱靶效应，因为肌肉生长抑制素/激活素受体广泛分布于许多非肌肉组织中。我们的研究表明，肌因子不仅抑制横纹肌的生长，而且还调节垂体发育和生长激素（GH）在肝脏中的作用。使用一种新的肌生长抑制素无效的标签保留模型（Jekyll小鼠），我们确定了Jekyll小鼠的垂体干细胞、过渡扩增细胞和祖细胞的异质池在出生后比野生型小鼠的池消耗得更快。这与生长激素、催乳素和分泌这些激素的细胞（分别为生长激素和催乳素）水平的增加有关。重组肌肉生长抑制素也刺激生长激素的释放和基因表达的垂体细胞培养，虽然抑制催乳素的释放。在原代肝细胞中，重组肌肉生长抑制素阻断GH刺激的两种关键生长介质胰岛素样生长因子（IGF）1和酸不稳定亚基的表达，并增加抑制剂IGF结合蛋白-1的表达。与肌生长抑制素缺失（Mighty）小鼠相比，缺乏肌生长抑制素和肝脏IGF 1表达的模型（LID-o-Mighty小鼠）中的肌纤维尺寸较小，证明了这些发现的重要性。这些数据共同表明，肌肉生长抑制素可以调节垂体发育和功能，其在肌肉中的抑制作用可能部分通过减弱肝脏中的GH作用来介导。他们还表明，肌肉生长抑制素的循环药理学抑制剂可能会在这些组织和其他组织中产生意想不到的后果。
Circulating myostatin-attenuating agents are being developed to treat muscle-wasting disease despite their potential to produce serious off-target effects, as myostatin/activin receptors are widely distributed among many nonmuscle tissues. Our studies suggest that the myokine not only inhibits striated muscle growth but also regulates pituitary development and growth hormone (GH) action in the liver. Using a novel myostatin-null label-retaining model (Jekyll mice), we determined that the heterogeneous pool of pituitary stem, transit-amplifying, and progenitor cells in Jekyll mice depletes more rapidly after birth than the pool in wild-type mice. This correlated with increased levels of GH, prolactin, and the cells that secrete these hormones, somatotropes and lactotropes, respectively, in Jekyll pituitaries. Recombinant myostatin also stimulated GH release and gene expression in pituitary cell cultures although inhibiting prolactin release. In primary hepatocytes, recombinant myostatin blocked GH-stimulated expression of two key mediators of growth, insulin-like growth factor (IGF)1 and the acid labile subunit and increased expression of an inhibitor, IGF-binding protein-1. The significance of these findings was demonstrated by smaller muscle fiber size in a model lacking myostatin and liver IGF1 expression (LID-o-Mighty mice) compared with that in myostatin-null (Mighty) mice. These data together suggest that myostatin may regulate pituitary development and function and that its inhibitory actions in muscle may be partly mediated by attenuating GH action in the liver. They also suggest that circulating pharmacological inhibitors of myostatin could produce unintended consequences in these and possibly other tissues.