Role of BNIP3 and mitophagy in muscle atrophy and cancer cachexia

Project Summary The proposed research sets out to examine the role of BNIP3 and mitophagy in muscle atrophy during cancer cachexia that is prevalent in pancreatic ductal adenocarcinoma (PDAC). Using physiologically relevant genetically engineered mouse (GEM) models of PDAC, we examine how BNIP3 promotes atrophy of myofibers with a focus on its role in reducing mitochondrial mass to levels incompatible with sustained growth and homeostasis of specific myofiber types. We also examine how reconstitution of myofibers with different mutant forms of BNIP3 affects key signaling pathways and myofiber growth. We also address the stresses and signals that may explain induction of BNIP3 in muscle by growing PDAC tumor and if these explain the differential muscle atrophy seen between males and females. These mechanistic insights are then interrogated in human PDAC patient muscle samples to determine whether BNIP3 levels in patient muscle predicts the extent of cachexia and survival outcomes (Aim 1). Separately we address how muscle atrophy promotes pancreatic tumor growth and progression by examining how muscle atrophy increases the release of proteins and metabolites into the bloodstream at early stages of pancreatic cancer that may promote progression of benign PanIN lesions to PDAC and increased tumor growth. Finally, we examine whether such muscle-derived factors in the circulation could serve as reliable biomarkers of early-stage pancreatic cancer that will be important for earlier clinical intervention and longer-term survival outcomes for PDAC patients (Aim 2).