Significance statement

Cachexia is the immediate cause of death for 20-40% of cancer patients. Cachexia is characterized by tissue fibrosis. The impact of cachexia progression on skeletal muscle fibrosis is unknown. Additionally, how sex alters the cachexia-associated fibrotic response in skeletal muscle is unknown. The principal finding of this study was that while tumor burden is tightly correlated to cachexia progression in both sexes, fibrotic development was not. Females demonstrated mild collagen deposition early whereas males did not demonstrate collagen deposition until much later with a much more exaggerated response. The lack of SMAD 2 and 3 induction suggests a non-canonical signaling pathway is involved in ECM regulation during the progression of cachexia.