Differential Branched-Chain Amino Acid Metabolism in Tissues of Tumor-Bearing Male Mice

Cancer cachexia is a multifactorial syndrome characterized by involuntary loss of skeletal muscle and adipose tissue that is often resistant to nutritional support. The branched-chain amino acids (BCAA: leucine, isoleucine, and valine) stimulate protein synthesis, yet BCAA-targeted therapies have yielded limited clinical benefit and inconsistent results. This might be related to altered metabolism of BCAA in cachexia. In this study, a C26 tumor allograft mouse model was used to examine how tumor burden alters BCAA metabolism across tumor tissue, liver, kidney, adipose tissue and skeletal muscle. Tumor tissue at 4 weeks exhibited higher BCAA levels and elevated branched-chain α-ketoacid dehydrogenase (BCKD) activity compared to samples collected at 2 weeks. At 4 weeks, skeletal muscles from tumor-bearing mice showed reduced BCAA concentrations relative to control. In contrast, liver and adipose tissue did not demonstrate uniform reductions in BCAA content, indicating tissue-specific metabolic responses. Multiple peripheral tissues also displayed lower expression of the L-type amino acid transporter 1 (LAT1) and alterations in downstream mechanistic target of rapamycin complex 1 (mTORC1) signaling. Notably, the soleus muscle maintained elevated phosphorylated S6 (P-S6) levels despite reduced BCAA availability, suggesting muscle-specific adaptations. These findings demonstrate distinct tumor and peripheral tissue alterations in BCAA handling in C26 tumor bearing mice. The observed changes in BCAA metabolism may underlie the limited success of BCAA-based interventions in cachexia and highlight the need for therapies that address both tumor and host metabolism.