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

Early human evidence such as case series or small samples is exploring possible benefits.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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

Evidence level

Early human evidence such as case series or small samples is exploring possible benefits.

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