Examining the role of neurogranin in calcineurin activation in rodent skeletal muscle

检查神经颗粒素在啮齿动物骨骼肌钙调神经磷酸酶激活中的作用

• 批准号: RGPIN-2019-05833
• 负责人: Fajardo, ValAndrew
• 金额: $ 1.68万
• 依托单位: Brock University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=679241
• 关键词: Examining; role; neurogranin; calcineurin; activation

Skeletal muscle, which accounts for a large proportion of our body mass, is not only important for movement and exercise but is also important for other daily functions including energy metabolism. As such maintaining muscle mass is vital to everyday living, and fortunately, our muscle cells have a unique ability to repair itself in the face of damaging stress through a process called muscle regeneration. ******Calcium is a very powerful signal in skeletal muscle biology/physiology as it activates not only muscle contraction but also a number of proteins that can help to improve exercise performance and our muscle's ability to grow and repair itself. One critical protein involved in calcium signalling in our muscle cells, in fact all of our cells, is calmodulin (CaM), which becomes activated with increased cellular calcium. Once activated, CaM can turn on a number of other proteins (downstream targets), such as calcineurin, which has been shown to enhance fatigue resistance and our muscle's ability to grow and regenerate. Surprisingly, despite the well-known importance of CaM in calcium signalling and skeletal muscle biology/physiology, we know very little with respect to how CaM is regulated in our muscle cells. In contrast, we know much more about how CaM is regulated in our brain and neuronal cells with the discovery and characterization of several CaM-binding proteins that can physically interact with CaM leading to either increased or decreased activation of CaM's downstream targets. One protein in particular is neurogranin (Ng), which, when it binds to CaM, keeps it away from its other downstream targets, like calcineurin, thereby preventing its activation. ******Recently, we have found that Ng is not only expressed in brain and neuronal cells but also can be found in our muscle cells where it can bind to CaM. However, we still have not figured out how exactly Ng works to regulate CaM in skeletal muscle and whether or not it can influence exercise performance, muscle growth, and repair. Thus, a major long-term objective of this research program is to determine the role of Ng as a CaM regulator in our muscle cells. For this objective, we will use genetically modified mice that do not have Ng in their muscles, and we will perform a number of laboratory techniques to figure out what happens to CaM and calcineurin signalling in muscle, and the impact on the muscle's ability to contract, grow and repair. Overall, this basic research will build a better understanding of the regulation of CaM in skeletal muscle and could lead to the exploration of other CaM binding proteins in skeletal muscle biology/physiology. This work could have important implications that extend into a number of fields such as exercise performance and muscle aging because of CaM and calcineurin's role in regulating fatigue and muscle repair.

骨骼肌占我们身体质量的很大一部分，不仅对运动和锻炼很重要，而且对其他日常功能也很重要，包括能量代谢。因此，保持肌肉质量对日常生活至关重要，幸运的是，我们的肌肉细胞具有独特的能力，可以通过称为肌肉再生的过程在面对破坏性压力时进行自我修复。钙是骨骼肌生物学/生理学中一个非常强大的信号，因为它不仅激活肌肉收缩，还激活许多蛋白质，有助于提高运动表现和肌肉的生长和修复能力。在我们的肌肉细胞中，实际上是我们所有的细胞中，参与钙信号传导的一种关键蛋白质是钙调蛋白（CaM），它随着细胞钙的增加而被激活。一旦激活，CaM可以打开许多其他蛋白质（下游靶点），如钙调神经磷酸酶，它已被证明可以增强抗疲劳性和我们肌肉的生长和再生能力。令人惊讶的是，尽管钙调素在钙信号传导和骨骼肌生物学/生理学中的重要性是众所周知的，但我们对钙调素在肌肉细胞中的调节方式知之甚少。相比之下，我们知道更多关于钙调素是如何在我们的大脑和神经元细胞的钙调素结合蛋白的发现和表征，可以与钙调素物理相互作用，导致增加或减少激活钙调素的下游目标。一种特别的蛋白质是神经颗粒蛋白（Ng），当它与CaM结合时，使其远离其他下游靶点，如钙调神经磷酸酶，从而防止其激活。** 最近，我们发现Ng不仅在脑和神经元细胞中表达，而且还可以在我们的肌肉细胞中发现，它可以与CaM结合。然而，我们仍然没有弄清楚Ng是如何调节骨骼肌中的CaM的，以及它是否会影响运动表现、肌肉生长和修复。因此，这项研究计划的一个主要长期目标是确定Ng作为我们肌肉细胞中CaM调节剂的作用。为了实现这一目标，我们将使用肌肉中没有Ng的转基因小鼠，我们将执行一些实验室技术来弄清楚肌肉中CaM和钙调神经磷酸酶信号传导发生了什么，以及对肌肉收缩，生长和修复能力的影响。总的来说，这项基础研究将建立一个更好地了解钙调素在骨骼肌中的调节，并可能导致其他钙调素结合蛋白在骨骼肌生物学/生理学的探索。这项工作可能具有重要的意义，延伸到许多领域，如运动表现和肌肉老化，因为钙调蛋白和钙调神经磷酸酶在调节疲劳和肌肉修复中的作用。