Immunoproteasomes in Skeletal Muscle Pathologies: Emerging Roles, Conflicting Evidence, and Future Directions

Highlights: What are the main findings? Immunoproteasomes (IMPs) act as a double-edged sword in muscle biology; they promote protein quality control and muscle differentiation under normal or early disease conditions, but they can drive muscle wasting when persistently activated. Excessive IMP activity fosters chronic inflammation and harmful crosstalk between immune and muscle cells, thereby worsening degeneration. What is the implication of the main findings? Targeting IMPs with selective inhibitors holds therapeutic promise in skeletal muscle diseases and experimental models of muscle loss. However, in skeletal muscle disorders, inhibition may be a mixed blessing, potentially reducing damaging inflammation but at the cost of impairing muscle maintenance and repair. Skeletal muscle pathologies, including sarcopenia, inflammatory myopathies, and various muscular dystrophies, are strongly influenced by chronic low-grade inflammation and impaired proteostasis. Immunoproteasomes (IMPs), inducible proteolytic complexes activated by pro-inflammatory cytokines, are emerging as regulators linking immune signaling to protein quality control. Evidence suggests that IMPs have paradoxical, context-dependent roles in skeletal muscle. On one hand, they can support proteostasis and muscle regeneration under stress; on the other, persistent activation may sustain cytokine production, antigen presentation, and maladaptive immune–muscle interactions, promoting chronic inflammation and muscle wasting. Selective IMP inhibitors, such as ONX 0914 and KZR-616, display potent anti-inflammatory effects in preclinical models of autoimmune myositis and muscle atrophy. Yet, their use in skeletal muscle pathologies is controversial; while inhibition may dampen harmful immune activation, it could also impair muscle repair and proteostasis. This review summarizes current findings, highlights key contradictions, and explores unresolved questions about the role of IMPs in skeletal muscle pathologies. We emphasize the need for a deeper understanding of IMP-mediated mechanisms in skeletal muscle pathology and strategies combining selective inhibitors to enhance therapeutic efficacy while minimizing adverse effects. IMPs thus represent both a promising and potentially risky therapeutic target, with outcomes highly dependent on disease context.