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<p>Muscle atrophy around joints is a common issue for people with osteoarthritis (OA), but its causes are poorly understood. Here we demonstrate that chronic inflammation in quadriceps muscle coincides with OA in mice, characterized by an increase in macrophages, activation of inflammatory pathways and tissue vascularization. We show that, during OA progression, macrophages progressively exhibit increasing phenotypes of senescence and promote muscle atrophy through paracrine induction of ferroptosis. Mechanistically, iron overload-induced mitochondrial damage results in reduced asparagine metabolites, impairing coenzyme Q10 (CoQ10) synthesis by inhibiting mTORC1–HMGCR signaling. Ultimately, this cascade enhances lipid peroxidation and promotes ferroptosis in skeletal muscle cells. We show that the cardiac medication CoQ10 can attenuate muscle atrophy by inhibiting ferroptosis, thereby reducing pathological damage to OA joints. Our findings offer insights for the potential management of muscle atrophy in patients with OA.</p>

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Senescent macrophages induce ferroptosis in skeletal muscle and accelerate osteoarthritis-related muscle atrophy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月27日

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  • Wei Xiang,
  • Tongyi Zhang,
  • Bingfei Li,
  • Song Li,
  • Bin Zhang,
  • Shunzheng Fang,
  • Lifeng Chen,
  • Yunquan Gong,
  • Bo Huang,
  • Daibo Feng,
  • Jinhui Wu,
  • Jing Yuan,
  • Yaran Wu,
  • Xiaojing Yan,
  • Runze Jin,
  • Xiaoqi Zhang,
  • Xiangqin Fang,
  • Jiqin Lian,
  • Lin Chen,
  • Siru Zhou,
  • Zhenhong Ni

摘要

Muscle atrophy around joints is a common issue for people with osteoarthritis (OA), but its causes are poorly understood. Here we demonstrate that chronic inflammation in quadriceps muscle coincides with OA in mice, characterized by an increase in macrophages, activation of inflammatory pathways and tissue vascularization. We show that, during OA progression, macrophages progressively exhibit increasing phenotypes of senescence and promote muscle atrophy through paracrine induction of ferroptosis. Mechanistically, iron overload-induced mitochondrial damage results in reduced asparagine metabolites, impairing coenzyme Q10 (CoQ10) synthesis by inhibiting mTORC1–HMGCR signaling. Ultimately, this cascade enhances lipid peroxidation and promotes ferroptosis in skeletal muscle cells. We show that the cardiac medication CoQ10 can attenuate muscle atrophy by inhibiting ferroptosis, thereby reducing pathological damage to OA joints. Our findings offer insights for the potential management of muscle atrophy in patients with OA.