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Background <p>Intervertebral disc degeneration (IVDD) is the primary pathological driver of chronic low back pain. While the mechanical role of skeletal muscle in spinal stability is well-established, its paracrine influence on IVDD—specifically via exosomes—remains poorly understood. This study investigated whether senescent skeletal muscle cell-derived exosomes (sSkM-Exos) aggravate metabolic dysregulation in nucleus pulposus cells (NPCs) and explored the underlying molecular mechanisms.</p> Methods <p>Senescence was induced in skeletal muscle cells (SkMCs) using hydrogen peroxide (H₂O₂), and sSkM-Exos were isolated via differential centrifugation and characterized. The internalization of sSkM-Exos by NPCs was observed. In vitro, the effects of sSkM-Exos on NPCs proliferation, senescence, apoptosis, and extracellular matrix (ECM) metabolism (COL2, ACAN, MMP13, and ADAMTS5) were evaluated. The involvement of the p38MAPK pathway was assessed using the inhibitor SB203580. <i>In vivo</i>, the impact of sSkM-Exos was validated using a rat IVDD model, monitored by disc height, MRI T2-weighted signaling, and histological analysis.</p> Results <p>We induced senescent skeletal muscle cells (SkMCs) with hydrogen peroxide (H₂O₂), extracted and identified sSkM-Exos via differential centrifugation. Our findings demonstrate that sSkM-Exos can be internalized by NPCs. In vitro, sSkM-Exos enhanced H₂O₂-induced NPC proliferation inhibition, senescence, apoptosis, and extracellular matrix (ECM) imbalance (downregulated COL2/ACAN, upregulated MMP13/ADAMTS5). Mechanistically, these effects were associated with p38MAPK activation; the p38MAPK inhibitor SB203580 partially reversed these impairments. <i>In vivo</i>, local sSkM-Exos injection was observed to exacerbate disc height loss and histological degeneration in a rat IVDD model.</p> Conclusions <p>In conclusion, sSkM-Exos were found to contribute to NPC senescence and ECM imbalance, likely through the activation of the p38MAPK pathway. These findings propose a cross-tissue regulatory network that supplements the traditional biomechanical model with a molecular perspective under experimental conditions. This study offers a new dimension to our understanding of IVDD pathogenesis and suggests that targeting sSkM-Exos or the p38MAPK pathway may hold promise as a therapeutic strategy to mitigate IVDD.</p>

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Exosomes derived from senescent skeletal muscle cells aggravate nucleus pulposus cell metabolic dysregulation via p38MAPK pathway for promoting intervertebral disc degeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月16日

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  • Xiaowei Ma,
  • Weiqi Zhang,
  • Han Yin,
  • Dazhuang Miao,
  • Xianda Gao,
  • Chunxu Fu,
  • Wei Chen,
  • Zhiyong Hou,
  • Qi Zhang,
  • Yingze Zhang,
  • Di Zhang

摘要

Background

Intervertebral disc degeneration (IVDD) is the primary pathological driver of chronic low back pain. While the mechanical role of skeletal muscle in spinal stability is well-established, its paracrine influence on IVDD—specifically via exosomes—remains poorly understood. This study investigated whether senescent skeletal muscle cell-derived exosomes (sSkM-Exos) aggravate metabolic dysregulation in nucleus pulposus cells (NPCs) and explored the underlying molecular mechanisms.

Methods

Senescence was induced in skeletal muscle cells (SkMCs) using hydrogen peroxide (H₂O₂), and sSkM-Exos were isolated via differential centrifugation and characterized. The internalization of sSkM-Exos by NPCs was observed. In vitro, the effects of sSkM-Exos on NPCs proliferation, senescence, apoptosis, and extracellular matrix (ECM) metabolism (COL2, ACAN, MMP13, and ADAMTS5) were evaluated. The involvement of the p38MAPK pathway was assessed using the inhibitor SB203580. In vivo, the impact of sSkM-Exos was validated using a rat IVDD model, monitored by disc height, MRI T2-weighted signaling, and histological analysis.

Results

We induced senescent skeletal muscle cells (SkMCs) with hydrogen peroxide (H₂O₂), extracted and identified sSkM-Exos via differential centrifugation. Our findings demonstrate that sSkM-Exos can be internalized by NPCs. In vitro, sSkM-Exos enhanced H₂O₂-induced NPC proliferation inhibition, senescence, apoptosis, and extracellular matrix (ECM) imbalance (downregulated COL2/ACAN, upregulated MMP13/ADAMTS5). Mechanistically, these effects were associated with p38MAPK activation; the p38MAPK inhibitor SB203580 partially reversed these impairments. In vivo, local sSkM-Exos injection was observed to exacerbate disc height loss and histological degeneration in a rat IVDD model.

Conclusions

In conclusion, sSkM-Exos were found to contribute to NPC senescence and ECM imbalance, likely through the activation of the p38MAPK pathway. These findings propose a cross-tissue regulatory network that supplements the traditional biomechanical model with a molecular perspective under experimental conditions. This study offers a new dimension to our understanding of IVDD pathogenesis and suggests that targeting sSkM-Exos or the p38MAPK pathway may hold promise as a therapeutic strategy to mitigate IVDD.