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B0092 tumor-bearing mice are a new model for the study of cachexia in head and neck cancer | American Journal of Physiology-Cell Physiology | American Physiological Society Introduction: Head and neck cancer (HNC) accounts for ~4% of all cancers but causes ~15,000 deaths annually in the U.S. Over 40% of HNC patients present with cachexia, a severe comorbidity associated with skeletal muscle defects, worsened treatment response, and poor outcomes. The mechanisms behind HNC cachexia remain unclear, partly due to limited small animal models. This study characterizes functional and molecular features of cachexia in a novel preclinical model using tobacco-induced B0092 oral squamous cell carcinoma in C57BL/6J mice. Methods: C2C12 myotubes were exposed to various concentrations of B0092 conditioned media (CM) to assess effects on myotube diameter and expression of muscle-specific ubiquitin ligases (MuRF−1, Atrogin−1). C57BL/6J male and female mice were implanted with B0092 cells (5x105 cells) to investigate musculoskeletal effects of HNC. RNA sequencing of muscle identified gene signatures associated with cachexia. Results: Myotubes treated with B0092 CM showed atrophy already at 25% CM (−21%, p<0.01), along with elevated MuRF-1 (+81%, p<0.05) and Atrogin-1 (+27%, p<0.05). B0092 tumor growth in male mice led to muscle atrophy, reduced strength (−36%, p<0.001), and lower bone mineral density (−8%, p<0.01). Muscle atrophy correlated with increased MuRF-1 (+1.96-fold, p<0.05) and Atrogin-1 (+1.97-fold, p<0.05). Female mice exhibited moderate cachexia despite similar tumor size. RNA sequencing of muscle in male B0092 hosts revealed mitochondrial dysfunction and upregulation of proteasome- and translation-related pathways, supporting a shift toward protein degradation and impaired energy metabolism. Conclusion: These findings suggest that B0092-bearing mice are valuable to uncover novel molecular pathways and potential therapeutic targets for HNC cachexia. https://journals.physiology.org/doi/abs/10.1152/ajpcell.00374.2025