Grant: Discovery Grants Program - Individual

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.