Deubiquitinase YOD1 Inhibition Suppresses DEX- and Denervation-Induced Muscle Atrophy Through MAFbx Destabilization.

BACKGROUNDS: Muscle atrophy, characterized by progressive loss of muscle mass and function, is driven by muscle-specific E3 ligases MAFbx and MuRF1. While transcriptional regulation of E3 ligases is documented, the mechanism of their regulation by the ubiquitin-proteasome system remains unclear. This study aims to identify a deubiquitinase (DUB) regulating these E3 ligases and reveal the mechanisms underlying the mitigation of muscle atrophy through inhibition of the discovered DUB. METHODS: Differentiated C2C12 myotubes were screened using siRNAs to identify DUB genes that can regulate muscle atrophy. Muscle fibre cross-sectional area (CSA), grip strength and gene expression (MAFbx, MyoD, etc.) were evaluated in muscle atrophy-induced mouse model. Human translational relevance was analysed using GTEx skeletal muscle data. RESULTS: ), correlating with enriched proteostasis (NES = 1.51)-related and muscle development (NES = -1.44)-related transcriptional signatures. CONCLUSIONS: Our study indicates that YOD1 inhibition destabilizes MAFbx protein levels, leading to protection against DEX- and denervation-induced muscle atrophy. Integration of human GTEx data further supports the translational relevance of YOD1 as a regulator of muscle fibre homeostasis. This study provides new insights into the post-translational regulation of muscle-specific E3 ligases and presents evidence showing that targeting YOD1 is a promising therapeutic approach for the prevention and treatment of muscle atrophy.