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 (BCAAs: leucine, isoleucine, and valine) stimulate protein synthesis, yet BCAA-targeted therapies have yielded limited clinical benefit and inconsistent results. This might be related to the 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 wk exhibited higher BCAA levels and elevated branched-chain α-keto acid dehydrogenase (BCKD) activity compared to samples collected at 2 wk. At 4 wk, skeletal muscles from tumor-bearing mice showed reduced BCAA concentrations relative to controls. 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.NEW & NOTEWORTHY This is the first study to profile branched-chain α-keto acid (BCKA) levels together with branched-chain amino acid (BCAA) metabolism across multiple tissues in a cancer cachexia model. Tumor progression was associated with higher BCAA levels. Some peripheral tissues showed BCAA depletion, and all peripheral sites exhibited reduced expression of the L-type amino acid transporter 1 (LAT1). These tissue-specific adaptations reveal systemic metabolic reprogramming and may explain the limited efficacy of BCAA-based therapies.