Endothelial Signaling in Exercise Metabolism

PROJECT SUMMARY Exercise is a powerful strategy to improve skeletal muscle metabolism that can both prevent and reverse disease. However, the complex signaling that drives the immediate and long-term changes in muscle metabolism is incompletely understood. Skeletal muscle is composed of numerous cell types (e.g., myocytes, vascular endothelial cells, pericytes, immune cells, etc.). In response to exercise stress, these cells "talk" to each other to orchestrate the increased energy production needed by the skeletal muscle. Understanding the signaling initiated and the pathways activated with cell type clarity will provide the molecular resolution necessary to unravel the protective effects of exercise. Our long-term goal is to understand intercellular skeletal muscle signaling initiated in response to exercise, thus informing strategies to promote health and prevent disease. Reactive oxygen species (ROS) are fast-acting, transient molecules recognized for their ability to initiate signaling cascades. The current proposal builds upon our K01 research, where we have identified a ROSproducer, NADPH oxidase 4 (NOX4), as a critical initiator of skeletal muscle metabolic responses to exercise. lmportanUy, this enzyme is most highly expressed in the vascular endothelial cells of skeletal muscle. If we remove this enzyme from only the endothelium, we observe a blunted metabolic response to acute exercise. We have previously shown that endothelial NOX4 increases expression and activity of endothelial nitric oxide synthase (eNOS). Based on these observations, the current proposal seeks to understand if eNOS lies downstream of NOX4 in mediating skeletal muscle responses to exercise. Therefore, we propose to uncover the role of eNOS in skeletal muscle mitochondrial metabolism and determine whether eNOS and nitric oxide production activate exercise-induced mitophagy. We will utilize innovative tools to address these questions and expect this project to reveal novel information regarding exercise-endothelial signaling. These studies will generate new hypotheses and will advance the Craige Lab research program by uncovering the underlying pathways influenced by eNOS. Ultimately, we hope these findings will contribute to the development of targeted exercise interventions and potentially even provide a foundation for treatment strategies based on exercise as medicine.