Mg2+ Modulates H3K27me3 Demethylation via KDM6A to Regulate Myoblast Differentiation and Crosstalk with Osteoclasts

Muscle injury and regeneration mechanisms following bone fractures, which are common in orthopedic conditions, remain incompletely understood. Improving patient prognosis could significantly benefit from metal debris derived from fracture fixation materials that promote muscle repair and prevention; however, the underlying mechanisms are poorly understood. In this study, we unveiled an unexpected role of Mg2+ in regulating repair responses and aging in injured CTX-induced muscles. Supporting this discovery, genetic models in C2C12 cells, both gain- and loss-of-function, demonstrated that muscle-specific Mg2+ supplementation enhanced myoblast differentiation, a process dependent on the H3K27me3 demethylase KDM6A rather than on KDM6B. Additionally, we observed that Mg2+ present in myoblasts inhibited excessive osteoclast activation, partially reversing their tendency to promote muscle atrophy. Our findings illuminate a muscle-bone crosstalk mechanism that bridges the gap between muscle dysfunction and bone injury. This crosstalk represents a potential long-term solution to fractures and disuse muscle atrophy.