Grant: Discovery Grants Program - Individual

INTRODUCTION: Skeletal muscle accounts for 40-50% of mammalian body mass and is important for functional mobility, temperature regulation, and metabolic homeostasis. Through the activation and inactivation of various cellular pathways, skeletal muscle can adapt to many different stressors such as regular exercise and muscle disuse. This `plasticity' is an important feature for muscle as it allows this tissue to match the energetic demands of regular use or disuse, which can in part be mediated by secondary messengers such as calcium - the activating stimulus of muscle contraction. The long-term goal of my research program is to understand the role that various calcium regulatory proteins may have on influencing skeletal muscle plasticity. Recently, we have discovered the presence of a protein named neuronatin (NNAT) in mouse skeletal muscle. While we have shown that NNAT regulates the calcium pump in muscle called SERCA, it's role in skeletal muscle may be more widespread, and thus requires further investigation. Indeed, our preliminary results show that NNAT regulates muscle size and strength, whereby mice that do not have NNAT show signs of muscle loss and weakness. However, the mechanisms behind how NNAT controls muscle size and function remain unknown. We have reasons to believe that this may be due to an overactivation of glycogen synthase kinase 3 (GSK3), which is an enzyme that we have shown negatively regulates muscle size and strength. Thus, my short-term objectives are to investigate the role of NNAT in skeletal muscle focusing on its regulation of muscle size, strength, GSK3 signalling, and the potential influence of biological sex. SCIENTIFIC APPROACH: To execute our research aims, we will use a combination of in vivo and ex vivo techniques and 3 genetically modified mouse models. To assess muscle strength, we will measure treadmill endurance and isolated muscle force production and fatigability. Muscle size and fibre type will be assessed via immunofluorescent microscopy and DXA scans for body composition. To assess muscle plasticity, we will employ NASA's model of simulated microgravity - hindlimb suspension with and without a reloading phase. Western blotting will be used to assess GSK3 signalling and its downstream targets. IMPACT: By gaining a better understanding of the role of NNAT in skeletal muscle, our work will reveal a new and pivotal player in the regulation and maintenance of skeletal muscle. We anticipate that our work, focusing on the biological role of NNAT, will have implications for improving muscle performance across the lifespan. Using cutting-edge technologies and unique genetically modified models, the trainees in my lab will gain the necessary skills and experience to set them as leaders in Canada working for academia and/or industry.