154 Elucidating the function of muscle-resident macrophages in cancer cachexia

Objectives/Goals: Cancer cachexia is a wasting condition common in pancreatic cancer, marked by loss of muscle, fat, and bone and driven by inflammation. Immune signals contribute to this damage. This study examines how muscle-resident macrophages may regulate muscle loss in pancreatic cancer cachexia. Methods/Study Population: To identify resident macrophages in cachectic muscle, Lyve1Cre-Rosa26;TdTomato mice were orthotopically transplanted with KPCML1 pancreatic cancer cells. Resident macrophages were analyzed via flow cytometry and immunohistochemistry. For muscle-specific macrophage ablation, lyve1-DTR mice (C57BL/6 background) received tumor cell injections followed by intramuscular diphtheria toxin (DTA) in the TA muscle. Quantitative RT-PCR assessed gene expression from whole muscle lysates and flow-sorted TdTomato+ cells. Results/Anticipated Results: We show that the population of muscle-resident macrophages increased as tumor burden increased. Further findings reveal that the ablation of the resident population of macrophages exacerbates muscle loss, suggesting that muscle-resident macrophages exude a protective phenotype on skeletal myofibers. This was confirmed with increased expression of atrophy biomarkers, MuRF1 and Atrogin-1, in muscles from DTA-injected mice. Additionally, preliminary data revealed an expansion of Toll-like receptor 7 (TLR7) expression in muscle-resident macrophages, suggesting that TLR7 signaling may contribute to their phenotypic regulation in cachexia. Discussion/Significance of Impact: Results suggest muscle-resident macrophages protect against cachexia-induced atrophy via anti-inflammatory activity. Future work will define their signals and targets. Given TLR7 upregulation, we will test if TLR7 signaling regulates their phenotype and contributes to muscle atrophy.