Bckdk-Mediated Branch Chain Amino Acid Metabolism Reprogramming Contributes to Muscle Atrophy during Cancer Cachexia.

Abstract

SCOPE:

Branched chain amino acids (BCAAs) are essential amino acids and important nutrient signals for energy and protein supplementation. The study uses muscle-specific branched-chain α-keto acid dehydrogenase kinase (Bckdk) conditional knockout (cKO) mice to reveal the contribution of BCAA metabolic dysfunction to muscle wasting.

METHOD AND RESULTS:

Muscle-specific Bckdk-cKO mice are generated through crossbreeding of Bckdkf/f mice with Myf5Cre mice. Lewis lung cancer (LLC) tumor transplantation is used to establish the cancer cachexia model. The occurrence of cancer cachexia is accelerated in the muscle-specific Bckdk-cKO mice after bearing LLC tumor. Wasting skeletal muscle is characterized by increased protein ubiquitination degradation and impaired protein synthesis. The wasting muscle gastrocnemius is mechanized as a distinct BCAA metabolic dysfunction. Based on the atrophy phenotype resulting from BCAA metabolism dysfunction, the optimized BCAA supplementation improves the survival of cancer cachexia in muscle-specific Bckdk-cKO mice bearing LLC tumors, and improves the occurrence of cancer cachexia. The mechanism of BCAA supplementation on muscle mass preservation is based on the promotion of protein synthesis and the inhibition of protein ubiquitination degradation.

CONCLUSIONS:

Dysfunctional BCAA metabolism contributes to the inhibition of protein synthesis and increases protein degradation in the cancer cachexia model of muscle-specific Bckdk-cKO mice bearing LLC tumors. The reprogramming of BCAA catabolism exerts therapeutic effects by stimulating protein synthesis and inhibiting protein degradation in skeletal muscle.

• Authors: Li Chen, Hong Zhang, Mengyi Chi, Yaxian Wang, Xinting Zhu, Leng Han, Bo Xin, Run Gan, Yixin Tu, Xipeng Sun, Jin Lu, Jie Li, Jinlu Huang, Jianping Zhang, Yonglong Han, Cheng Guo, Quanjun Yang
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Pg. e2300577 (Dec 27 2023) ISSN: 1613-4133 [Electronic] Germany
• PMID: 38150655 (Publication Type: Journal Article)
• Copyright: © 2023 Wiley-VCH GmbH.