NRF1/NFE2L1 orchestrates spatiotemporal regulation of protein degradation network in skeletal muscle

Abstract Skeletal muscle (SkM) relies on precise regulation of protein synthesis and degradation for functional integrity, with the ubiquitin-proteasome system (UPS) as a cornerstone of homeostasis. Nuclear factor (erythroid-derived 2)-like 1 (NFE2L1), a conserved CNC-bZIP transcription factor, integrates redox balance and proteasome gene expression, but its fiber-type-specific roles in SkM remain unclear. Here, we integrated multi-omics datasets from aging and sarcopenia cohorts to characterize the spatiotemporal activity of NFE2L1 in SkM. Genetic variants in NFE2L1 were significantly associated with lean muscle mass and grip strength in the UK Biobank. Striated muscle-specific Nfe2l1 knockout mice (Nfe2l1(SM)-KO) displayed age-dependent SkM atrophy characterized by preferential loss of Type IIb fibers, heightened inflammatory response, fat infiltration and regulated cell death (RCD). Proteomic, metabolomic, and lipidomic analyses unveiled a NFE2L1-driven regulatory network maintaining UPS function and metabolic homeostasis. Single-nucleus RNA sequencing revealed global UPS dysfunction and shifts in myonuclear states toward RCD-prone phenotypes in Nfe2l1(SM)-KO muscle. Pharmacological activation of proteasomes with rolipram partially mitigated atrophy in juvenile knockouts, and human aging SkM datasets confirmed conserved myonuclear state transitions. Collectively, NFE2L1 emerges as a pivotal spatiotemporal regulator of SkM proteostasis, bridging UPS maintenance with fiber-type integrity and offering therapeutic targets for age-related muscle decline.