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

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

  • Adv Sci (Weinh). 2026 May;13(25):e15362. doi: 10.1002/advs.202515362.
Xiaoyan Shao 1 2,  Pan Zhang 1 3 4 5,  Zhidan Fan 2,  Jiaquan Lin 1 6,  Xiang Chen 1 3 4 5,  Na Liu 1 3 4 5,  Wang Gong 1 3 4 5,  Yi He 1 3 4 5,  Yining Zhou 1 3 4 5,  Tianshu Shi 1 3 4 5,  Yong Shi 1 3 4 5,  Yuze Ma 1 3 4 5,  Wentian Gao 1 3 4 5,  Haosheng Wang 1 3 4 5,  Depeng Fang 1 3 4 5,  Chengzhi Wang 1 3 4 5,  Wenshu Wu 1 3 4 5,  Wenjin Yan 1 3 4 5,  Jianghui Qin 1 3 4 5,  Dongyang Chen 1 3 4 5,  Haiguo Yu 2,  Qing Jiang 1 3 4 5,  Baosheng Guo 1 3 4 5
Affiliations

Affiliations

  • 1 Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, P. R. China.
  • 2 Department of Rheumatology and Immunology, Children's Hospital of Nanjing Medical University, Nanjing, P. R. China.
  • 3 Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Nanjing, P. R. China.
  • 4 Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu, P. R. China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, P. R. China.
  • 6 Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P. R. China.
PMID: 41747076 DOI: 10.1002/advs.202515362
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.

Keywords

MiR‐125a‐5p; bone formation; extracellular vesicles; muscle atrophy; osteoporosis.

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