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

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，而且对包括能量代谢在内的其他日常功能也很重要。因此，维持肌肉质量对日常生活至关重要，幸运的是，我们的肌肉细胞有一种独特的能力，可以通过一种叫做肌肉再生的过程，在面对破坏性压力时进行自我修复。钙在骨骼肌生物学/生理学中是一个非常强大的信号，因为它不仅能激活肌肉收缩，还能激活一些蛋白质，这些蛋白质可以帮助提高运动表现，增强肌肉的生长和自我修复能力。在我们的肌肉细胞中，实际上是我们所有的细胞中，有一种与钙信号有关的关键蛋白质是钙调蛋白（CaM），它会随着细胞钙的增加而被激活。一旦被激活，CaM可以启动许多其他蛋白质（下游目标），如钙调磷酸酶，它已被证明可以增强抗疲劳能力和我们肌肉的生长和再生能力。令人惊讶的是，尽管CaM在钙信号传导和骨骼肌生物学/生理学中的重要性众所周知，但我们对CaM在肌肉细胞中的调节机制知之甚少。相比之下，随着几种CaM结合蛋白的发现和表征，我们对大脑和神经元细胞中CaM是如何被调节的有了更多的了解，这些蛋白可以与CaM相互作用，导致CaM下游靶点的激活增加或减少。一种特别的蛋白质是神经颗粒蛋白（Ng），当它与CaM结合时，使其远离其他下游目标，如钙调磷酸酶，从而阻止其激活。最近，我们发现Ng不仅在大脑和神经元细胞中表达，而且在我们的肌肉细胞中也可以发现它可以与CaM结合。然而，我们仍然没有弄清楚Ng究竟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，本研究计划的一个主要长期目标是确定Ng在肌肉细胞中作为CaM调节因子的作用。为此，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的CaM和钙调磷酸酶信号发生了什么，以及对肌肉收缩、生长和修复能力的影响。总之，这项基础研究将有助于更好地理解CaM在骨骼肌中的调控作用，并可能导致骨骼肌生物学/生理学中其他CaM结合蛋白的探索。由于CaM和钙调磷酸酶在调节疲劳和肌肉修复方面的作用，这项工作可能会对许多领域产生重要影响，比如运动表现和肌肉衰老。

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.