A novel multi-omics approach to explore mechanisms of lean mass recovery - MIRA Abstract This proposed research explores the complex phenomenon of cachexia, a condition characterized by severe weight loss and muscle wasting that occurs in various terminal illnesses such as sepsis, cancer, and heart failure. Despite advancements in addressing underlying chronic illness, there remains a critical need to determine the mechanisms that can reverse lean mass losses during cachexia, which will inform the development of effective therapeutics for recovery. During endurance flight and fasting, migratory birds naturally experience dramatic reductions in lean body mass, in excess of what is experienced during cachexia, yet these animals rapidly recover muscle and organ mass losses quickly, with few functional consequences. This proposed research investigates the functional consequences of tissue loss in multiple organ systems, the metabolomic profile of catabolic and anabolic states, and the mechanisms of tissue regeneration in migratory birds with the goal of using this novel, natural model to discover new mechanisms associated with tissue anabolism. We propose to use innovative whole animal approaches to investigate lean body mass reductions, enabling longitudinal studies of organ system function, molecular mechanisms, and recovery processes using this novel, avian natural system. Over the next five years, our goals include combining functional assessments with metabolomics and transcriptomics to uncover unique mechanistic determinants of recovery. Key questions to be addressed involve understanding structural- functional relationships, analyzing metabolite and cytokine responses during lean mass loss, and elucidating molecular pathways driving tissue degradation and remodeling. By leveraging expertise in organismal physiology, metabolism, and molecular biology, we aim to contribute significantly to the field's knowledge base. Ultimately, our research strives to inform the development of novel models and therapeutic strategies for combating cachexia and promoting recovery in patients with debilitating conditions.
