Dysregulation of the ubiquitin–proteasome system in aging skeletal muscle

Protein homeostasis (proteostasis) is essential for maintaining skeletal muscle integrity, and its disruption is a central feature of aging related sarcopenia. The ubiquitin–proteasome system (UPS) is the primary pathway responsible for selective protein degradation in muscle. However, its regulation during physiological aging remains incompletely understood. Most studies have focused on muscle-specific E3 ubiquitin ligases, particularly MuRF1 and MAFbx/atrogin-1, which are widely used as molecular markers of muscle atrophy. However, changes in E3 ligase expression do not consistently correspond to proteasome activity, suggesting a disconnect between ubiquitination signals and proteolytic capacity in aging muscle. In this review, we synthesize current evidence on age-related alterations in key components of the UPS, including proteasome activity, E3 ubiquitin ligases, and deubiquitinating enzymes (DUBs). We highlight that these components are differentially regulated across muscles and conditions. We further discuss DUBs as an additional regulatory layer that remains poorly understood in skeletal muscle aging. These findings emphasize the need to move beyond single-marker interpretations of UPS activity. Overall, current evidence indicates that aging skeletal muscle is characterized not by a simple increase in protein degradation, but by multi-layered dysregulation of proteostasis networks. A more integrated evaluation of UPS components will be required to better understand protein turnover in aging muscle. • Aging muscle shows dysregulated proteostasis rather than uniform activation. • E3 ligase expression does not consistently reflect proteasome activity. • Evidence for UPS regulation remains muscle- and context-dependent. • DUBs (USP2, USP19, and UCHL1) may contribute to muscle atrophy. • DUBs remain poorly characterized in skeletal muscle aging.