UBR2 Targets Myosin Heavy Chain IIb and IIx for Degradation: Molecular Mechanism Essential for Cancer-Induced Muscle Wasting

Authors

Song Gao
Guohua Zhang
Zicheng Zhang
James Z Zhu
Li Li
Yong Zhou
George G Rodney
Reem S Abo-Zahrah
Lindsey Anderson
Jose M Garcia
Yong Tae Kwon
Yi-Ping Li

Publication Date

10-25-2022

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abstract

Cancer cachexia is a lethal metabolic syndrome featuring muscle wasting with preferential loss of fast-twitching muscle mass through an undefined mechanism. Here, we show that cancer induces muscle wasting by selectively degrading myosin heavy chain (MHC) subtypes IIb and IIx through E3 ligase UBR2-mediated ubiquitylation. Induction of MHC loss and atrophy in C2C12 myotubes and mouse tibialis anterior (TA) by murine cancer cells required UBR2 up-regulation by cancer. Genetic gain or loss of UBR2 function inversely altered MHC level and muscle mass in TA of tumor-free mice. UBR2 selectively interacted with and ubiquitylated MHC-IIb and MHC-IIx through its substrate recognition and catalytic domain, respectively, in C2C12 myotubes. Elevation of UBR2 in muscle of tumor-bearing or free mice caused loss of MHC-IIb and MHC-IIx but not MHC-I and MHC-IIa or other myofibrillar proteins, including α-actin, troponin, tropomyosin, and tropomodulin. Muscle-specific knockout of UBR2 spared KPC tumor-bearing mice from losing MHC-IIb and MHC-IIx, fast-twitching muscle mass, cross-sectional area, and contractile force. The rectus abdominis (RA) muscle of patients with cachexia-prone cancers displayed a selective reduction of MHC-IIx in correlation with higher UBR2 levels. These data suggest that UBR2 is a regulator of MHC-IIb/IIx essential for cancer-induced muscle wasting, and that therapeutic interventions can be designed by blocking UBR2 up-regulation by cancer.

Keywords

Animals, Mice, Actins, Cachexia, Muscle Fibers, Skeletal, Muscle, Skeletal, Myosin Heavy Chains, Neoplasms, Nonmuscle Myosin Type IIB, Tropomodulin, Tropomyosin, Troponin, Ubiquitin-Protein Ligases, cancer cachexia, UBR2, ubiquitylation, MHC-IIb, MHC-IIx

Comments

Supplementary Materials

PMID: 36252004