Voluntary wheel running selectively preserves skeletal muscle during pancreatic cancer cachexia despite persistent systemic alterations

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with cancer cachexia, involving alterations across multiple physiological systems. Whether distinct exercise paradigms similarly influence these compartments remains unclear. We compared voluntary wheel running (VWR) and treadmill running (TR) using an integrative physiological approach in a murine model of pancreatic cancer cachexia. Methods Male C57BL/6J mice bearing UN-KC-6141 pancreatic tumor cells were allocated to inactive control (CaCTL), VWR or TR groups and compared with healthy controls. Tumor progression, body composition, skeletal muscle, adipose tissue, hepatic metabolism, systemic inflammation, energy expenditure and behavior were assessed. Analysis of covariance determined whether tissue-mass differences remained evident after adjustment for tumor burden. Results UN-KC-6141 tumors induced a systemic cachectic phenotype involving skeletal muscle and adipose tissue wasting, hepatic metabolic remodeling, systemic inflammation and behavioral alterations. VWR slowed tumor growth, reduced final tumor mass, improved the body-weight trajectory and preserved lean and skeletal muscle mass, whereas TR did not reproduce these adaptations. Greater gastrocnemius mass with VWR remained evident after adjustment for tumor mass, indicating that reduced tumor burden alone was insufficient to account for muscle preservation. In contrast, adipose tissue wasting, hepatic metabolic remodeling and systemic inflammation remained largely unaffected. TR was also associated with a less favorable body-weight trajectory and greater fat mass loss than in inactive tumor-bearing mice. Exploratory metabolic phenotyping revealed distinct feeding, sleep and resting energy expenditure patterns between the two exercise paradigms. Conclusions VWR selectively preserved skeletal muscle within a persistently altered systemic environment, whereas the TR protocol used here did not reproduce these adaptations. These findings reveal tissue-specific exercise responsiveness during pancreatic cancer cachexia and highlight exercise paradigm characteristics as determinants of tumor-host adaptation.