生物谷：利用特定的遺傳差異，科學(xué)家創(chuàng)造了小鼠中的“施瓦辛格”,，它的肌肉質(zhì)量超過普通小鼠四倍,。該研究成果有助于探索人類肌肉萎縮癥,、艾滋病以及癌癥引起的肌肉損失。相關(guān)論文發(fā)表在近期的PLoS ONE上,。
進(jìn)行該項(xiàng)研究的是美國(guó)約翰·霍普金斯大學(xué)醫(yī)學(xué)院的Se-Jin Lee,，他創(chuàng)造的肌肉鼠有兩個(gè)主要的變異——它們不能制造肌肉抑制素（myostatin），但卻能大量生產(chǎn)卵泡抑制蛋白（follistatin）,。由于肌肉抑制素會(huì)限制肌肉發(fā)育,，因此缺乏它的小鼠會(huì)多長(zhǎng)肌肉；同時(shí),，卵泡抑制蛋白會(huì)影響抑制肌肉發(fā)育的蛋白起作用,，也就是說，兩方面因素都促使小鼠的肌肉更多更強(qiáng)壯,。
進(jìn)一步研究發(fā)現(xiàn),，肌肉鼠與正常鼠的肌纖維存在很大不同，前者肌纖維的大小超過后者的兩倍,，而且在數(shù)量上也比后者多73%,。
研究人員認(rèn)為，在缺乏肌肉抑制素的條件下卵泡抑制蛋白仍然能夠促進(jìn)肌肉發(fā)育,，這說明小鼠體內(nèi)存在不止一種肌肉調(diào)控機(jī)制,。此外，小鼠體內(nèi)的肌肉抑制素水平要高于人類,，這也表明該蛋白對(duì)人類并非特別重要,。Lee說，“在人類體內(nèi)幾乎探測(cè)不到肌肉抑制素,，很明顯,，另有別的因素存在。”
如果生物學(xué)家能夠在人體內(nèi)確定更多的卵泡抑制蛋白可以綁定的蛋白,，就有望導(dǎo)致新的促進(jìn)人類肌肉發(fā)育或者維持肌肉的藥物出現(xiàn),。此外，新的研究成果的意義還在于培育更加長(zhǎng)肉的家畜,。不過,，Lee特別強(qiáng)調(diào)，他不希望新的研究成果成為運(yùn)動(dòng)員提升肌肉水平的工具,。（科學(xué)網(wǎng) 任霄鵬/編譯）
原始出處:
PLoS one
Received: June 1, 2007; Accepted: July 25, 2007; Published: August 29, 2007
Quadrupling Muscle Mass in Mice by Targeting TGF-ß Signaling Pathways
Se-Jin Lee*
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Myostatin is a transforming growth factor-ß 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-ß 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.
Figure 3. Comparison of wild type and F66/Mstn−/− mice.
In previous studies, we showed that the increase in muscle mass in Mstn−/− mice results from a combination of increased fiber numbers and increased fiber sizes [2]. To determine whether the same is true for the additional muscle mass seen upon introduction of the F66 transgene, I carried out morphometric analysis of the gastrocnemius/plantaris muscles. As shown in Table 2 and Figure 2c, total fiber number and mean fiber diameter were increased by about 48% and 19%, respectively, in Mstn−/− mice compared to wild type mice. As the cross-sectional area of the muscle would be expected to be roughly proportional to the square of the diameter, increased fiber diameter in Mstn−/− mice would correspond to an approximately 43% increase in fiber mass. Hence, muscle fiber hyperplasia and hypertrophy appear to contribute roughly equally to give the overall doubling of gastrocnemius/plantaris mass in Mstn−/− mice. In contrast, a similar analysis of F66 transgenic mice revealed that although total fiber number was increased slightly (16%), the overall increase in gastrocnemius/plantaris mass resulted almost entirely from muscle fiber hypertrophy (93% increase in cross-sectional area). In mice in which the F66 transgene was combined with the Mstn null mutation, the two phenotypes appeared to be additive; that is, the quadrupling of muscle mass in F66/Mstn−/− mice resulted from an approximately 73% increase in fiber number and 117% increase in fiber cross-sectional area. These results suggest that the additional muscle mass induced by follistatin in Mstn null mice results from inhibition of additional ligands that act predominantly to regulate muscle fiber growth.
