Quadrupling Muscle Mass in Mice by Targeting TGF-β Signaling Pathways
Quadrupling Muscle Mass in Mice by Targeting TGF-β Signaling Pathways
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DOI：
10.1371/journal.pone.0000789
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发表时间：
2007-08-29
期刊：
影响因子：
3.7
通讯作者：
Lee, Se-Jin
中科院分区：
文献类型：
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作者：
Lee, Se-Jin
肌生长抑制素是一种转化生长因子-β家族成员，通常起限制骨骼肌生长的作用。通过基因工程改造而缺乏肌肉生长抑制素活性的小鼠全身肌肉质量约为对照组的两倍，在牛、羊、狗和肌肉生长抑制素基因自然发生功能丧失突变的人身上也观察到了类似的效果。因此，对于开发能够抑制肌肉生长抑制素活性的试剂用于农业和人类治疗应用存在相当大的兴趣。我们以前表明，肌肉生长抑制素结合蛋白，卵泡抑素，可以诱导肌肉质量显着增加时，在小鼠中作为转基因过表达。为了确定卵泡抑素的这种作用是否仅仅是由于抑制肌肉生长抑制素的活性，我分析了这种转基因在肌肉生长抑制素缺失小鼠中的作用。携带促滤泡素抑制素转基因的小鼠（-/-）的肌肉质量约为野生型小鼠的四倍，表明存在与肌生长抑制素具有相似活性的其他肌肉质量调节剂。对肌肉质量的最大影响是在纯合子的母亲的后代中观察到的MSTs突变，提高了肌肉生长抑制素本身或下游调节因子可能通常从母体转移到胎儿循环的可能性。这些发现表明，通过操纵TGF-β信号通路增加肌肉生长的能力比以前认识到的要广泛得多，并表明肌肉质量可能至少部分地由肌肉生长抑制素的全身作用模式控制。
Myostatin is a transforming growth factor-beta family member that normally acts to limit skeletal muscle growth. Mice genetically engineered to lack myostatin activity have about twice the amount of muscle mass throughout the body, and similar effects are seen in cattle, sheep, dogs, and a human with naturally occurring loss-of-function mutations in the myostatin gene. Hence, there is considerable interest in developing agents capable of inhibiting myostatin activity for both agricultural and human therapeutic applications. We previously showed that the myostatin binding protein, follistatin, can induce dramatic increases in muscle mass when overexpressed as a transgene in mice. In order to determine whether this effect of follistatin results solely from inhibition of myostatin activity, I analyzed the effect of this transgene in myostatin-null mice. Mstn(-/-) mice carrying a follistatin transgene had about four times the muscle mass of wild type mice, demonstrating the existence of other regulators of muscle mass with similar activity to myostatin. The greatest effect on muscle mass was observed in offspring of mothers homozygous for the Mstn mutation, raising the possibility that either myostatin itself or a downstream regulator may normally be transferred from the maternal to fetal circulations. These findings demonstrate that the capacity for increasing muscle growth by manipulating TGF-beta signaling pathways is much more extensive than previously appreciated and suggest that muscle mass may be controlled at least in part by a systemic mode of action of myostatin.