Mg²⁺ modulates H3K27me3 demethylation via KDM6A to regulate myoblast differentiation and osteoclast crosstalk

Despite the high prevalence of bone fractures in orthopedic practice, the mechanisms underlying muscle injury and regeneration remain poorly understood. Metal ions released from fracture fixation materials may improve patient outcomes by promoting muscle repair and preventing atrophy; however, the underlying mechanisms remain unclear. In this study, we investigated the role of magnesium ions (Mg²⁺) in regulating muscle regeneration in cardiotoxin-induced muscle injury. Mg²⁺ supplementation enhanced myogenic differentiation in C2C12 cells, as demonstrated by gain- and loss-of-function experiments targeting lysine-specific demethylase 6 A (KDM6A). Mechanistically, this effect was mediated by KDM6A-dependent demethylation of trimethylated lysine 27 on histone H3 (H3K27me3), rather than by KDM6B. Furthermore, Mg²⁺-treated myoblasts inhibited excessive osteoclast activation, partially reversing osteoclast-induced promotion of muscle atrophy. These findings reveal a KDM6A-dependent epigenetic mechanism by which Mg²⁺ coordinates muscle regeneration and modulates muscle-bone crosstalk. Collectively, this study provides a mechanistic basis for the therapeutic potential of magnesium-based biomaterials in mitigating disuse-induced muscle atrophy and improving outcomes following bone injury.