生物谷:利用特定的遗传差异,科学家创造了小鼠中的“施瓦辛格”,它的肌肉质量超过普通小鼠四倍。该研究成果有助于探索人类肌肉萎缩症、艾滋病以及癌症引起的肌肉损失。相关论文发表在近期的PLoS ONE上。
进行该项研究的是美国约翰·霍普金斯大学医学院的Se-Jin Lee,他创造的肌肉鼠有两个主要的变异——它们不能制造肌肉抑制素(myostatin),但却能大量生产卵泡抑制蛋白(follistatin)。由于肌肉抑制素会限制肌肉发育,因此缺乏它的小鼠会多长肌肉;同时,卵泡抑制蛋白会影响抑制肌肉发育的蛋白起作用,也就是说,两方面因素都促使小鼠的肌肉更多更强壮。
进一步研究发现,肌肉鼠与正常鼠的肌纤维存在很大不同,前者肌纤维的大小超过后者的两倍,而且在数量上也比后者多73%。
研究人员认为,在缺乏肌肉抑制素的条件下卵泡抑制蛋白仍然能够促进肌肉发育,这说明小鼠体内存在不止一种肌肉调控机制。此外,小鼠体内的肌肉抑制素水平要高于人类,这也表明该蛋白对人类并非特别重要。Lee说,“在人类体内几乎探测不到肌肉抑制素,很明显,另有别的因素存在。”
如果生物学家能够在人体内确定更多的卵泡抑制蛋白可以绑定的蛋白,就有望导致新的促进人类肌肉发育或者维持肌肉的药物出现。此外,新的研究成果的意义还在于培育更加长肉的家畜。不过,Lee特别强调,他不希望新的研究成果成为运动员提升肌肉水平的工具。(科学网 任霄鹏/编译)
原始出处:
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.