Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle

Postmitotic skeletal muscle critically depends on tightly regulated protein degradation to maintain proteomic stability. Impaired macroautophagy/autophagy-lysosomal or ubiquitin-proteasomal protein degradation causes the accumulation of damaged proteins, ultimately accelerating muscle dysfunction with age. While in vitro studies have demonstrated the complementary nature of these systems, their interplay at the organism levels remains poorly understood. Here, our study reveals novel insights into this complex relationship in autophagy-deficient skeletal muscle. We demonstrated that despite a compensatory increase in proteasome level in response to autophagy impairment, 26S proteasome activity was not proportionally enhanced in autophagy-deficient skeletal muscle. This functional deficit was partly attributed to reduced ATP levels to fuel the 26S proteasome. Remarkably, we found that activation of EIF4EBP1, a crucial inhibitor of cap-dependent translation, restored and even augmented proteasomal function through dual mechanisms. First, genetically activating EIF4EBP1 enhanced both ATP-dependent 26S proteasome and ATP-independent 20S proteasome activities, thereby expanding overall protein degradation capacity. Second, EIF4EBP1 activation caused muscle fiber transformation and increased mitochondrial biogenesis, thus replenishing ATP levels for 26S proteasome activation. Notably, the improved performance of the 20S proteasome in EIF4EBP1-activated skeletal muscle was attributed to an increased abundance of the immunoproteasome, a subtype specially adapted to function under oxidative stress conditions. This dual action of EIF4EBP1 activation preserved proteomic integrity in autophagy-deficient skeletal muscle. Our findings uncover a novel role of EIF4EBP1 in improving protein quality control, presenting a promising therapeutic strategy for autophagy-related muscular disorders and potentially other conditions characterized by proteostatic imbalance.