PLASMA AND SKELETAL MUSCLE METABOLIC PATHWAYS ASSOCIATED WITH WEIGHT LOSS, LOW MUSCLE, OR POOR FUNCTION IN CANCER

Cancer cachexia (muscle wasting leading to functional impairment) is experienced by most individuals with cancer and increases with age. There are no approved treatments in the U.S./E.U. because Phase III trials have failed to achieve functional endpoints. Identification of metabolites/metabolic pathways related to poor functional performance may reveal therapeutic targets but metabolomics analyses in cancer cachexia have only examined weight loss and/or muscle mass. We characterized metabolomic perturbations in plasma and abdominal wall skeletal muscle from men (n=75; median age=65) with cancer undergoing laparotomy and tested associations with function (handgrip strength “HGS” and stair climb power “SCP” assessed within two weeks pre-surgery), muscle mass (CT L3: cross-sectional area “CT-CSA”), or weight loss (six months pre-surgery). We hypothesized that metabolomic signatures in plasma and muscle would be associated with poorer HGS and SCP and alterations would be distinguishable from associations with weight loss or lower CT-CSA. Spearman correlations and pathway analyses (global test) were performed using “R.” Benjamini-Hochberg false discovery rate (FDR)< 0.1 indicated significance. Lipid/fatty acid peroxidation/transport/metabolism was disrupted in muscle with lower CT-CSA (FDR≤0.09) and in plasma (FDR≤0.07) and muscle (trend; FDR=0.14) with weight loss. Phenylalanine/tyrosine/tryptophan biosynthesis (p=0.045) and amino/nucleotide sugar metabolism (p=0.018) were disrupted in muscle with worse SCP, but not after adjustment (FDR>0.5). Significant/trending dysregulation was not detected in plasma with worse SCP or in muscle/plasma with worse HGS. Lipid metabolism was associated with cancer-related weight loss and low muscle mass. Future studies should analyze metabolomics in activity/mobility-related muscles to elucidate metabolite/pathway dysregulation in cancer-related functional impairment.