Atrophic Skeletal Muscle‐Derived Extracellular Vesicles Transfer miR‐125a‐5p to Inhibit Bone Formation in Osteoporosis during Aging

ABSTRACT Understanding how skeletal muscle influences bone formation is essential for uncovering the mechanisms of muscle‐bone communication and developing therapies for osteoporosis. Here, we demonstrate that extracellular vesicles (EVs) derived from atrophic skeletal muscle (Aged‐SKM‐EVs) inhibit bone formation during aging. Utilizing a muscle‐specific EV tracking transgenic mouse model, we found that Aged‐SKM‐EVs were significantly increased and taken up by osteoblasts in bone during aging. Notably, pharmacological blockade of muscle EV generation via a skeletal muscle‐targeted delivery of GW4869 significantly restored osteoblast activity and alleviated bone loss in aged mice. Functional studies revealed that Aged‐SKM‐EVs suppressed bone formation and inhibited osteogenic differentiation both in vivo and in vitro. Mechanistically, we identified miR‐125a‐5p as a key cargo enriched in EVs from sarcopenic patients and aged mice. Muscle‐specific overexpression of miR‐125a‐5p inhibited osteogenesis and exacerbated muscle atrophy and bone loss, whereas silencing miR‐125a‐5p in skeletal muscle effectively reversed these effects. Further investigation demonstrated that miR‐125a‐5p inhibits osteogenic differentiation by directly targeting Sirt7 in preosteoblasts, thereby disrupting SIRT7‐mediated histone deacetylation at the Sp7 promoter and suppressing Sp7 transcription. Our findings reveal a novel endocrine pathway from muscle to bone mediated by EV‐associated miRNA and highlight miR‐125a‐5p as a promising therapeutic target for sarcopenia‐related osteoporosis.