Differential impact of cancer- and chemotherapy-induced cachexia: a comparative analysis in a preclinical model of colorectal cancer by biological sex.

Cancer cachexia is a wasting condition characterized by muscle loss and reduced quality of life in cancer patients. Although biological sex differences in the progression of cancer cachexia have been increasingly recognized, their role during chemotherapy-treated cancer cachexia remains largely unexplored. We evaluated such potential differences in male and female mice implanted subcutaneously with Colon-26 (C26) allografts. Our novel approach to disentangle the effects of chemotherapy consisted of administering two cycles of 75% of the maximum tolerated dose of 5-fluorouracil, cisplatin, or paclitaxel in the presence and absence of cancer (n = 6-11/condition). Muscles and organs were collected 25 days after tumor implant, and protein turnover markers, gene expression through RNA sequencing, and mitochondrial function were evaluated in gastrocnemius. A two-way factorial analysis was conducted to assess main effects and interactions across groups (P < 0.05). We demonstrate that chemotherapy exhibited preserved fat mass in males and maintained body weight in females. Chemotherapy elicited negative impacts on muscle in both sexes, even with a reduced or absent tumor burden. In males, protein synthesis was lower in the presence of cancer and chemotherapy without corresponding differences in atrogenes. Cluster analysis revealed largest differences in muscle transcriptome between cancer control and C26-paclitaxel in male mice, highlighting altered regulation of ubiquitin-mediated proteolysis. These findings point to divergent mechanisms during protein processing in endoplasmic reticulum regulation in muscle atrophy associated with cancer in the presence of chemotherapy. Our results highlight distinct mechanisms underlying cancer cachexia alone versus the addition of chemotherapy and further indicate that responses to chemotherapy differ between biological sexes.NEW & NOTEWORTHY Our study highlights critical differences in the mechanisms mediating muscle loss between cancer and chemotherapy-treated cancer, particularly those by which proteins are degraded and processed. Our data point to biological sex differences in the responsiveness to chemotherapy agents as well as the wasting response. Major differences were observed between sexes, specifically fat mass preservation in male mice and the preservation of body weight in female mice, both despite significant reduction in muscle mass.