Metabolic and inflammatory crosstalk underlying cancer-related fatigue (CRF) in a mouse model of breast cancer (BC)

Cancer-related fatigue (CRF) is among the most prevalent and debilitating side effects of breast cancer and its treatment in women, severely reducing adherence to treatment and quality of life. However, standardized, preclinical metrics for CRF remain poorly defined, impeding the development of therapeutic interventions. We hypothesized that breast cancer-induced physical fatigue is due to metabolic dysregulation in skeletal muscle mitochondria. Using the syngeneic E0771 mouse model of breast cancer, we characterized physical fatigue, assessed cytokine profiles, and performed targeted metabolomic analyses of muscle. Tumor-bearing mice showed significantly reduced survival and fat mass although overall body weight and lean mass were stable. Physical performance declined after three weeks of tumor growth as shown by reduced grip strength, maximum speed and peak oxygen consumption. Metabolic cage activity of mice revealed reduced oxygen consumption, carbon dioxide production, respiratory exchange ratio, energy expenditure, and water intake, consistent with suppressed metabolic function. Metabolomic profiling of skeletal muscle revealed upregulation of pipecolate and pyridoxamine, metabolites linked to amino acid metabolism and oxidative stress signaling, while key mitochondrial and antioxidant metabolites including glutathione, riboflavin and isocitrate were suppressed. These alterations suggest mitochondrial dysfunction, redox imbalance, and impaired energy production as contributors to the physical fatigue phenotype. These changes were accompanied by reduced IL1beta, IL-2, MIP-1alpha and increased IP-10 in the plasma implicating inflammation-driven metabolic reprogramming. Breast cancer induced coordinated inflammatory and metabolic changes in the skeletal muscle, disrupting mitochondrial pathways that contribute to physical fatigue. This study identifies distinct metabolic signatures associated with CRF and highlights mitochondrial pathways as promising targets for therapeutic intervention to improve the quality of life in breast cancer patients.