Aquaporins: A hole in our understanding of hydrogen peroxide regulation

水通道蛋白：我们对过氧化氢调节理解的一个漏洞

• 批准号: BB/T002115/1
• 负责人: Richard Barrett-Jolley
• 金额: $ 49.07万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT002115%2F1
• 关键词: Aquaporins; hole; our; understanding; hydrogen

Lay Summary:There has been great interest in the idea that free radicals (and other chemicals that are collectively called reactive oxygen species "ROS") contribute to loss of muscle performance and indeed a whole range of age-related disorders. We have lots of evidence that excessive production of one of these reactive species, hydrogen peroxide, can be damaging to muscle structure and function. Since loss of muscle mass and strength is a leading cause of immobility in older people in the developed world it is surprising that there are no published studies of how hydrogen peroxide passes through skeletal muscle cell membranes (sarcolemma) and no previous attempts to see if blocking such transport can preserve muscle function. In this project, we will close this fundamental knowledge gap.In the past few years, it has become clear that the major route of transport of hydrogen peroxide through membranes in various non-muscle cells is the family of membrane protein channels called "aquaporins". Our pilot data confirm that aquaporins facilitate hydrogen peroxide membrane transport in skeletal muscle too.The existence of aquaporin proteins has been known for about 25 years now, but they were first thought of simply as the route of passage of water through membranes. In fact, the characterisation of these so-called "water channels" gained Prof Agre a Nobel Prize in 2003. Surprisingly, therefore, there have been only a few studies of muscle aquaporins and no studies of their role in the regulation of muscle hydrogen peroxide at all. This is perhaps because previously there had been a lack of appropriate research tools to study hydrogen peroxide in fine detail.Our group's unique combination of novel molecular tools and muscle degeneration models now allow us to answer a number of fundamental and important biological questions about hydrogen peroxide transport in skeletal muscle.(a) Which of the aquaporins are most important for hydrogen peroxide spread in muscles?(b) Does aquaporin regulation of hydrogen peroxide change with age or muscle injury?(c) Does block of muscle aquaporins promote maintenance of muscle function after neuromuscular injury? It is often assumed that free radicals are "bad" and "antioxidants" are good and that therefore block of aquaporins or elimination of peroxide would be beneficial to muscle function, however, this is a very simplistic view and needs validating. For example, some recent data support the possibility that hydrogen peroxide transport is critical to high-performance muscle function. Furthermore, there are dozens of common dietary substances that can block some of the aquaporin channels, many of these are so-called plant "polyphenols" and, coincidentally, better known for their antioxidant properties. So we need to answer these widely important biological questions urgently so that dieticians and those in medical research can start to develop more informed treatment strategies for age and injury-related muscle loss.

通俗摘要：人们对自由基(和其他化学物质统称为“ROS”)会导致肌肉功能丧失，甚至是一系列与年龄相关的疾病有很大的兴趣。我们有大量证据表明，其中一种活性物质过氧化氢的过量产生可能会损害肌肉的结构和功能。由于肌肉质量和力量的丧失是发达国家老年人行动不便的主要原因，令人惊讶的是，没有发表过关于过氧化氢如何通过骨骼肌细胞膜(肌膜)的研究，也没有以前尝试过阻止这种运输是否可以保护肌肉功能。在这个项目中，我们将弥合这一基本的知识鸿沟。在过去的几年里，人们已经清楚地看到，过氧化氢通过各种非肌肉细胞的膜转运的主要途径是被称为水通道蛋白的膜蛋白通道家族。我们的初步数据证实，水通道蛋白也促进了骨骼肌中过氧化氢的膜运输。水通道蛋白的存在已有约25年的历史，但最初被认为只是水通过膜的途径。事实上，对这些所谓“水道”的描述为阿格雷教授赢得了2003年的诺贝尔奖。因此，令人惊讶的是，只有几个关于肌肉水通道蛋白的研究，根本没有关于它们在肌肉过氧化氢调节中的作用的研究。这可能是因为之前缺乏适当的研究工具来详细研究过氧化氢。我们团队独特的新型分子工具和肌肉退化模型的组合现在使我们能够回答一些关于过氧化氢在骨骼肌中运输的基本和重要的生物学问题。(A)哪些水通道蛋白对过氧化氢在肌肉中的传播最重要？(B)水通道蛋白对过氧化氢的调节是否会随着年龄或肌肉损伤而改变？(C)肌肉水通道蛋白的阻断是否促进了神经肌肉损伤后肌肉功能的维持？人们通常认为自由基是“坏的”，而“抗氧化剂”是好的，因此阻断水通道蛋白或消除过氧化氢对肌肉功能是有益的，然而，这是一个非常简单的观点，需要验证。例如，最近的一些数据支持过氧化氢运输对高性能肌肉功能至关重要的可能性。此外，有几十种常见的饮食物质可以阻断一些水通道，其中许多是所谓的植物“多酚”，巧合的是，它们更为人所知的是它们的抗氧化特性。因此，我们迫切需要回答这些广泛重要的生物学问题，以便营养学家和医学研究人员能够开始为年龄和损伤相关的肌肉损失制定更明智的治疗策略。

项目成果

Extracellular Vesicle Production by Skeletal Muscle: Role in Neuromuscular Ageing

骨骼肌产生细胞外囊泡：在神经肌肉衰老中的作用

• DOI: 10.1016/j.freeradbiomed.2020.12.334
• 发表时间: 2021
• 期刊: Free Radical Biology and Medicine
• 影响因子: 7.4
• 作者: Hemmings K

Exosomal Signaling by Skeletal Muscle: Role in Neuromuscular Ageing

骨骼肌的外泌体信号传导：在神经肌肉衰老中的作用

• DOI: 10.1016/j.freeradbiomed.2020.10.268
• 发表时间: 2020
• 期刊: Free Radical Biology and Medicine
• 影响因子: 7.4
• 作者: Hemmings K

Development of age-related loss of muscle mass and function - role of oxidative DNA damage repair systems

与年龄相关的肌肉质量和功能丧失的发展——氧化DNA损伤修复系统的作用

• DOI: 10.1016/j.freeradbiomed.2020.12.335
• 发表时间: 2021
• 期刊: Free Radical Biology and Medicine
• 影响因子: 7.4
• 作者: Kumiscia K

Pro-inflammatory Cytokines Drive Deregulation of Potassium Channel Expression in Primary Synovial Fibroblasts

• DOI: 10.3389/fphys.2020.00226
• 发表时间: 2020-03-24
• 期刊: FRONTIERS IN PHYSIOLOGY
• 影响因子: 4
• 作者: Haidar, Omar;O'Neill, Nathanael;Barrett-Jolley, Richard
• 通讯作者: Barrett-Jolley, Richard

Power Analysis HR/BP 2 from Systemic application of the transient receptor potential vanilloid-type 4 antagonist GSK2193874 induces tail vasodilation in a mouse model of thermoregulation

功率分析 HR/BP 2 来自瞬时受体电位香草酸 4 型拮抗剂 GSK2193874 的系统应用，在小鼠体温调节模型中诱导尾部血管舒张

• DOI: 10.6084/m9.figshare.19958299
• 发表时间: 2022
• 作者: O'Brien F