Immunoproteasome subunit PSMB8 promotes skeletal muscle regeneration by regulating macrophage phenotyping switch in mice

Immunoproteasomes regulate the degradation of ubiquitin-coupled proteins and cell differentiation. However, its precise role in skeletal muscle regeneration remains unclear. In this study, we found that expression of the immunoproteasome subunit, PSMB8, increased significantly in young muscles after cardiotoxin-induced injury, whereas its expression was downregulated in injured aged mice. Genetic knockout or pharmacological inhibition of the immunoproteasome subunit, PSMB8, resulted in impaired muscle regeneration and increased interstitial fibrosis. PSMB8 inhibition by short interfering RNA (siRNA) or inhibitor decreased the differentiation ability of myoblasts. There was increased infiltration of inflammatory cells, especially Ly6C^hi proinflammatory macrophages, in <i>Psmb8</i> deficient muscles. In vitro, <i>Psmb8-</i>deficient macrophages expressed higher levels of proinflammatory cytokines and lower levels of anti-inflammatory cytokines after phagocytosis of myoblast debris, which was associated with increased activation of the NF-κB signaling pathway. Inhibition of the NF-κB pathway improves the regeneration ability and attenuates interstitial fibrosis in <i>Psmb8-</i>deficient muscles after injury. The overexpression of <i>Psmb8</i> by adenovirus could also improve the regenerative ability of aged muscles.<b>NEW & NOTEWORTHY</b> The immunoproteasome subunit, PSMB8, is essential for efficient muscle regeneration and may be a new therapeutic target for age-related muscle atrophy.