Project 454894

Maintenance of muscle through muscle regeneration is a critical aspect of human health. Indeed, defects in muscle regeneration are associated with numerous muscle-related diseases, such as muscular dystrophy and cancer-associated muscle atrophy (cachexia). In adults, muscle regeneration is carried out by satellite stem cells within muscle tissue. Like other stem cells, they are capable of either maintaining their stemness following cell division or committing to form differentiated tissue. The decision between these fates depends on the orientation of cell division, a phenomenon known as cell polarity. A careful balance of both types of cell division is needed, allowing for formation of new muscle tissue and maintenance of the stem cell pool following repeated bouts of regeneration. Although it is well known that inflammation during muscle injury plays a critical role in regeneration, little is known about how it impacts satellite stem cells and their polarity. However, preliminary and published data from us and others suggests polarity is defective during cachexia, which is characterized by chronic inflammation. Our goal is to better understand how inflammatory signaling affects stem cell polarity. To do so, we will screen inflammatory signaling molecules, known as cytokines, to determine which are capable of impacting satellite stem cell polarity. We will then determine the intracellular mechanisms by which these cytokines inhibit polarity. Finally, we will perform pre-clinical mouse studies to assess the feasibility of inhibiting these systems in satellite stem cells to restore their function and improve regeneration during cachexia. Collectively, these studies will provide new understanding of how inflammation can influence muscle regeneration, laying the groundwork for the development of future regenerative therapies.