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Grizzly bears spend many months in hibernation, but their muscles do not suffer from the lack of movement. In the journal “Scientific Reports”, a team led by Michael Gotthardt reports on how they manage to do this. The grizzly bears’ strategy could help prevent muscle atrophy in humans as well.

众所周知灰熊有冬眠这一习性,然而它们的肌肉却不会因为长达几个月的缺乏运动而萎缩。在Michael Gotthardt领导的研究团队的《科学报告》中,讲述了它们如何做到这一点的。灰熊的策略也可以帮助预防人类的肌肉萎缩。

A grizzly bear only knows three seasons during the year. Its time of activity starts between March and May. Around September the bear begins to eat large quantities of food. And sometime between November and January, it falls into hibernation. From a physiological point of view, this is the strangest time of all. The bear’s metabolism and heart rate drop rapidly. It excretes neither urine nor feces. The amount of nitrogen in the blood increases drastically and the bear becomes resistant to the hormone insulin.

一只灰熊只知道一年有三个季节。它的活动时间从三月到五月开始。九月左右,熊开始吃大量的食物蓄积能量。在十一月到一月之间的某个时候,它陷入了休眠状态。从生理的角度看,这是最奇怪的时刻。熊的新陈代谢和心率迅速下降。它既不排尿也不排泄粪便。血液中的氮含量急剧增加,而此时熊对胰岛素也不产生反应。



Understanding and copying the tricks of nature

了解和复制自然的窍门

“Muscle atrophy is a real human problem that occurs in many circumstances. We are still not very good at preventing it,” says the lead author of the study, Dr. Douaa Mugahid, once a member of Gotthardt’s research group and now a postdoctoral researcher in the laboratory of Professor Marc Kirschner of the Department of Systems Biology at Harvard Medical School in Boston.

“肌肉萎缩是在许多情况下都会发生真正的人类问题。而我们仍然不能很好的去应对它,”该研究的主要作者Douaa Mugahid博士说,Douaa Mugahi博士曾经是Gotthardt教授研究小组的成员,现在是波士顿哈佛医学院系统生物学系的Marc Kirschner教授实验室的博士后研究员。

“For me, the beauty of our work was to learn how nature has perfected a way to maintain muscle functions under the difficult conditions of hibernation,” says Mugahid. “If we can better understand these strategies, we will be able to develop novel and non-intuitive methods to better prevent and treat muscle atrophy in patients.”

Mugahid说:“对我来说,我们的工作之美在于学习自然如何完善了在困难的冬眠条件下维持肌肉功能的方法。” “如果我们能更好地理解这些策略,我们将能够开发出新颖且可靠的方法来更好地预防和治疗患者的肌肉萎缩。”

To understand the bears’ tricks, the team led by Mugahid and Gotthardt examined muscle samples from grizzly bears both during and between the times of hibernation, which they had received from Washington State University. “By combining cutting-edge sequencing techniques with mass spectrometry, we wanted to determine which genes and proteins are upregulated or shut down both during and between the times of hibernation,” explains Gotthardt.

为了了解熊的策略,由Mugahid和Gotthardt领导的团队在数个连续的冬天里检查了灰熊的肌肉样本,这是他们从华盛顿州立大学收到的。 Gotthardt解释道:“通过将先进的测序技术与质谱分析法相结合,我们希望确定在冬眠期间以哪些基因和蛋白质被上调或关闭。”

“This task proved to be tricky – because neither the full genome nor the proteome, i.e., the totality of all proteins of the grizzly bear, were known,” says the MDC scientist. In a further step, he and his team compared the findings with observations of humans, mice and nematode worms.

MDC的科学家说:“这项任务非常棘手-因为我们既不了解完整的基因组,也不了解蛋白质组,即不知道灰熊所有的蛋白质。”下一步,他和他的团队将这些发现与人类,小鼠和线虫蠕虫的观察结果进行了比较。



Tissue samples from bedridden patients
In order to find out which signaling pathways need to be activated in the muscle, Gotthardt and his team compared the activity of genes in grizzly bears, humans and mice. The required data came from elderly or bedridden patients and from mice suffering from muscle atrophy – for example, as a result of reduced movement after the application of a plaster cast. “We wanted to find out which genes are regulated differently between animals that hibernate and those that do not,” explains Gotthardt.

为了找出哪些信号通路需要在肌肉中激活,Gotthardt和他的团队比较了灰熊,人类和小鼠中基因的活性。所需数据来自老年患者或卧床不起的患者以及患有肌肉萎缩症的小鼠,例如打了石膏之后活动减少的病患。 Gotthardt解释说:“我们想找出相比于那些不冬眠的动物,冬眠动物的基因有哪些受到了调控。”

However, the scientists came across a whole series of such genes. To narrow down the possible candidates that could prove to be a starting point for muscle atrophy therapy, the team subsequently carried out experiments with nematode worms. “In worms, individual genes can be deactivated relatively easily and one can quickly see what effects this has on muscle growth,” explains Gotthardt.

但是,科学家们遇到了一系列这样的基因。为了缩小可能被证明是肌肉萎缩治疗起点的候选对象范围,研究小组随后进行了线虫蠕虫实验。 Gotthardt解释说:“在蠕虫中,单个基因可以相对轻松地失活,并且可以迅速看到其对肌肉生长的影响。”

A gene for circadian rhythms
With the help of these experiments, his team has now found a handful of genes whose influence they hope to further investigate in future experiments with mice. These include the genes Pdk4 and Serpinf1, which are involved in glucose and amino acid metabolism, and the gene Rora, which contributes to the development of circadian rhythms. “We will now examine the effects of deactivating these genes,” says Gotthardt. “After all, they are only suitable as therapeutic targets if there are either limited side effects or none at all.”

在这些实验的帮助下,他的团队现在已经发现了一些基因,他们希望通过这些基因的影响来进一步研究小鼠。其中包括参与葡萄糖和氨基酸代谢的基因Pdk4和Serpinf1,以及有助于昼夜节律发展的基因Rora。 Gotthardt说:“我们现在将研究使这些基因失活的作用。” “毕竟,只有在副作用有限或根本没有副作用的情况下,它们才适合作为靶向治疗。”