治疗老年性运动功能下降的新思路

0 Comments

A new treatment concept for age-related decline in motor function

Enhancement of motor function and muscle strength in aged mice by enhancing formation of neuromuscular junctions

神经肌肉接头的形成对老龄小鼠运动功能和肌力的影响

Date: 日期:August 17, 2020 2020年8月17日Source: 来源:The Institute of Medical Science, The University of Tokyo 东京大学医学研究所Summary: 摘要:A research group conducted experiments using aged mice to demonstrate that muscle denervation at the neuromuscular junction (NMJ, *1) could be appreciably offset by an NMJ formation-enhancing treatment that strengthened the motor function and muscle of aged mice. The results of this study suggest that NMJ formation-enhancing treatment may be effective to overcome motor impairment and muscle weakness associated with human aging. 一个研究小组用老年小鼠进行实验,证明在神经肌肉接点的肌肉去神经支配(NMJ,* 1)可以明显地被增强老年小鼠运动功能和肌肉的 NMJ 形成治疗所抵消。本研究结果提示,NMJ 形成促进治疗可能是克服运动障碍和肌肉无力与人类老化的有效方法Share: 分享:    FULL STORY 完整故事


In an aging society, one of the most important and urgent tasks of scientific research is to counteract the decline in motor function and muscle weakness that accompanies the aging process.

在人口老龄化社会中,解决随着年龄增长而出现的运动功能下降和肌肉无力的问题,是科学研究中最重要和最紧迫的任务之一。

A research group led by Professor Yuji Yamanashi of the Institute of Medical Science, the University of Tokyo, conducted experiments using aged mice to demonstrate that muscle denervation at the neuromuscular junction (NMJ, *1) could be appreciably offset by an NMJ formation-enhancing treatment that strengthened the motor function and muscle of aged mice.

东京大学医学研究所的 Yuji Yamanashi 教授领导的一个研究小组,用老龄小鼠进行实验,证明神经肌肉接点的肌肉去神经支配(NMJ,* 1)可以明显地被增强老龄小鼠运动功能和肌肉的 NMJ 形成治疗所抵消。

The results of this study suggest that NMJ formation-enhancing treatment may be effective to overcome motor impairment and muscle weakness associated with human aging.

本研究结果提示,NMJ 形成促进治疗可能是克服运动障碍和肌肉无力与人类老化的有效方法。

The results of this research were published in iScience on August 5, 2020.

这项研究的结果发表在2020年8月5日的《科学》杂志上。

The NMJ is the only “bond” that connects motor nerves to skeletal muscles

NMJ 是连接运动神经和骨骼肌的唯一“纽带”

In order to move the body, precise control of skeletal muscle contraction via motor nerves is required. The NMJ is the only “bond” that connects motor nerves to skeletal muscles (the neuromuscular synapse), and its loss means that motor functions including breathing cease to work.

为了移动身体,需要通过运动神经精确控制骨骼肌肉收缩。NMJ 是连接运动神经和骨骼肌(神经肌肉突触)的唯一“纽带” ,它的丧失意味着包括呼吸在内的运动功能停止工作。

The research group focused on “nerve detachment” aka “denervation” at NMJs, in which the motor nerve becomes separated from the NMJ, a process that progresses with aging.

研究小组的重点是在 NMJ 处的“神经分离” ,也就是“去神经支配” ,即运动神经从 NMJ 中分离出来,这是一个随着年龄增长而发展的过程。

As a result of the treatment given to aged mice to enhance the formation of NMJs, the following three points were verified:

通过对老龄小鼠进行促进 nmj 形成的治疗,以下三点得到了验证:

According to the research group, muscle denervation at the neuromuscular junction (NMJ), the essential synapse between motor neuron and skeletal muscle, is associated with age-related motor impairment. Therefore, improving muscle innervation at aged NMJs may be an effective therapeutic strategy for treating the impairment.

根据该研究小组的研究,运动神经元和骨骼肌之间的基本突触—- 神经肌肉接点的肌肉去神经支配(NMJ)与年龄相关的运动障碍有关。因此,改善老年 nmj 的肌肉神经支配可能是治疗该损害的有效策略。

They previously demonstrated that the muscle protein Dok-7 (*2) plays an essential role in NMJ formation, and, indeed, its forced expression in muscle enlarges NMJs. Moreover, therapeutic administration of an adeno-associated virus vector encoding human Dok-7 (DOK7 gene therapy) suppressed muscle denervation and enhanced motor activity in a mouse model of amyotrophic lateral sclerosis (ALS). Here, they show that DOK7 gene therapy significantly enhances motor function and muscle strength together with NMJ innervation in aged mice.

他们先前证明,肌肉蛋白 Dok-7(* 2)在 NMJ 的形成中起重要作用,事实上,它在肌肉中的强制表达扩大了 NMJ。此外,治疗性应用编码人类 Dok-7的腺相关病毒载体(DOK7基因疗法)抑制了肌萎缩性嵴髓侧索硬化症小鼠模型的肌肉失神经支配和运动活动增强。这里,他们表明 DOK7基因治疗显着增强老龄小鼠的运动功能和肌肉力量以及 NMJ 神经支配。

Furthermore, the treated mice showed greatly increased compound muscle action potential (CMAP) amplitudes compared to the controls, suggesting enhanced NMJ transmission. Thus, therapies aimed at enhancing NMJ innervation have potential for treating age-related motor impairment.

此外,治疗小鼠显示大大增加复合肌肉动作电位(CMAP)幅度相比,控制,提示增强 NMJ 传输。因此,以强化 NMJ 神经支配为目的的治疗对于治疗年龄相关性运动障碍具有潜力。

For details of the research, please see the paper.

有关这项研究的详细内容,请参阅论文。

Possibility of opening the way to NMJ formation-enhancing therapy using compounds

使用化合物开辟 NMJ 形成增强治疗途径的可能性

Yuji Yamanashi, the corresponding author of this research, Professor at the Institute of Medical Science, The University of Tokyo, said, “In this new study with mice, NMJ augmentation treatment was shown to be effective for age-related motor impairment and muscle weakness, which are serious problems in an aging society. It has great social significance in terms of presenting the possibilities.”

这项研究的通讯作者,东京大学医学科学研究所教授 Yuji Yamanashi 说: “在这项新的小鼠研究中,NMJ 增强疗法被证明对于老龄化社会中的严重问题——与年龄相关的运动障碍和肌肉无力——有效。它在展现可能性方面具有重大的社会意义。”

In addition, this study is not only a basic study of gene therapy using AAV-D7 (*3), but also serves as a proof of principle for opening the way to NMJ formation-enhancing therapy using compounds.

此外,本研究不仅是 AAV-D7(* 3)基因治疗的基础性研究,而且为化合物促进 NMJ 形成治疗开辟了原理性的证明。

The research group hopes that the findings of this research will be used in the future to promote many research efforts from various perspectives, such as translational research to overcome age-related motor impairment and muscular weakness, together with development of compounds with NMJ formation-enhancing effect.

该研究小组希望这项研究的成果能够在未来从多个角度推动许多研究工作,如转化研究,以克服与年龄有关的运动障碍和肌肉无力,以及开发具有 NMJ 形成促进作用的化合物。

This work was conducted as joint research with Dr. Noboru Ogiso at The National Center for Geriatrics and Gerontology (NCGG) and Dr. Noriyasu Ota and his colleagues at Biological Science Research, Kao Corporation in Japan.

这项研究是由日本国立长寿医疗研究中心的小木伸郎博士和日本花王公司生物科学研究所的大田 Noriyasu Ota 博士及其同事共同完成的。

Research Notes

研究笔记

(*1) NMJ (neuromuscular junction)

(* 1)新界南(神经肌肉接点)

The NMJ is a cholinergic synapse in mammals between a motor neuron and skeletal muscle, and is essential for motoneural control of skeletal muscle contraction.

神经突触是哺乳动物中介于运动神经元和骨骼肌之间的一种胆碱能突触,对于骨骼肌的运动神经控制至关重要。神经突触是肌肉收缩神经元和骨骼肌之间的一种神经元突触。

(*2) Dok-7

(* 2) Dok-7

Dok-7 (Downstream of kinases-7) is an essential cytoplasmic activator of the muscle-specific receptor tyrosine kinase MuSK, both of which are required for the formation and maintenance of NMJs.

Dok-7(kinases-7的下游)是肌肉特异性受体酪氨酸激酶麝香的重要胞浆激活剂,两者都是形成和维持 nmj 所必需的。

(*3) AAV-D7

(* 3) AAV-D7

AAV-D7 is a recombinant muscle-tropic adeno-associated virus (AAV) serotype 9 vector carrying the human DOK7 gene. The therapeutic administration of AAV-D7 -DOK7 gene therapy- induces augmented MuSK activation and enhances NMJ formation.

AAV-D7是一种携带人 DOK7基因的重组腺相关病毒(AAV)血清型9型载体。AAV-D7-DOK7基因治疗诱导增强 MuSK 活化,促进 NMJ 的形成。


发表评论

邮箱地址不会被公开。 必填项已用*标注