白血病诱导的恶病质由色氨酸代谢失调所驱动，导致肌肉再生能力受抑制

Cachectic muscle wasting occurs in many cancers but remains poorly defined in hematological malignancies. Leukaemia associated muscle loss is often exacerbated by chemotherapy, limiting treatment efficacy and presenting a poor prognosis, yet its mechanisms remain unclear. We aim to define drivers of leukaemia induced muscle atrophy, focusing on metabolic dysregulation. Using a syngeneic acute myeloid leukaemia mouse model in which C57/Bl6 mice received MN1-overexpressing cells intravenously, we observed significant weight loss independent of food intake. Gastrocnemius mass was significantly reduced in tumor-bearing mice compared to non-tumor bearing controls. H&E staining identified structural abnormalities and reduced fiber area. RNA seq followed by confirmation with RT-qPCR showed strong induction of atrophy genes TRIM63 and FBXO32, consolidating atrophy within our model. To assess muscle regeneration, we used a Pax7-CreERT2 reporter mouse model expressing tdTomato, allowing visualization of the satellite cells. Despite similar satellite-cell numbers in AML and controls, AML muscles displayed higher overall integrated density, indicating increased Pax7 expression and therefore satellite cell activation. However, centrally located nuclei were absent, revealing impaired regenerative activity. To define metabolic contributors, we performed NMR on serum. Tumor-bearing mice showed broad depletion of amino acids, however kynurenine pathway metabolites were strongly elevated. Metabolites of this pathway such as kynurenate and quinolinate have been linked to enhanced oxidative stress and aryl hydrocarbon receptor signaling that can impair muscle stem cell function and promote catabolism (Grishanova A. and Perepechaeva M. 2024). Due to altered amino acid levels and the RNA seq data, we examined transporter mRNA expression in the muscles and found significant upregulation of LAT1 during disease progression, which exchanges intracellular glutamine for branched-chain amino acids and tryptophan, the initial metabolite of the kynurenine pathway. Furthermore, cytokine profiling revealed multiple elevated atrophy-associated mediators, including GDF-15, IL-6, CXCL2, and CD14. IL17A was most elevated (7-fold), consistent with its reported role in lung cancer cachexia via JAK2/STAT3 signaling (Ying L. et al 2022). In summary, we have used a multi-omic approach to elucidate metabolic and cytokine changes that occur during leukaemia to drive cachexia. Future work will investigate the mechanism that drives these leukaemia-induced alterations to identify potential therapeutic interventions.