DIfferential Branched-Chain Amino Acid Metabolism in Tissues of Tumour-Bearing Mice

Abstract

Cancer cachexia is a multifactorial syndrome characterized by the involuntary loss of skeletal muscle and adipose tissue, 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. In this study, a C26 colon cancer mouse model was used to examine how tumor burden alters BCAA metabolism across skeletal muscle, liver, kidney, and adipose tissue. Tumors accumulated BCAA and showed increased oxidation of these amino acids, whereas peripheral sites displayed widespread BCAA depletion, reduced expression of the amino acid (AA) transporter LAT1, and suppression of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Notably, the soleus muscle maintained mTORC1 activity despite reduced BCAA availability, suggesting fiber-type-specific adaptations. These findings indicate that tumors act as metabolic sinks, diverting systemic AA away from host tissues. Such reprogramming 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 and NoteworthyThis is the first study to profile branched-chain -keto acid (BCKA) levels together with branched-chain amino acid (BCAA) metabolism across multiple tissues in a cancer cachexia model. Tumors accumulated BCAA while some peripheral sites showed depletion, and all peripheral tissues exhibited reduced expression of the transporter LAT1. These tissue-specific adaptations reveal systemic metabolic reprogramming and may explain the limited efficacy of BCAA-based therapies.