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 using male and female mice implanted subcutaneously with Colon-26 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 following 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 chemotherapy exhibited preserved fat mass in males while maintained body weight in females. Chemotherapy elicited negative impacts on muscle in both sexes, even in 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 responses to chemotherapy differ between biological sexes.