2. Academic Validation
  3. Senescent macrophages induce ferroptosis in skeletal muscle and accelerate osteoarthritis-related muscle atrophy

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

  • Nat Aging. 2025 Jul;5(7):1295-1316. doi: 10.1038/s43587-025-00907-0.
Wei Xiang # 1,  Tongyi Zhang # 1 2,  Bingfei Li # 1,  Song Li # 3,  Bin Zhang # 3,  Shunzheng Fang 1,  Lifeng Chen 1,  Yunquan Gong 1,  Bo Huang 1,  Daibo Feng 1,  Jinhui Wu 1,  Jing Yuan 4,  Yaran Wu 5,  Xiaojing Yan 4,  Runze Jin 1,  Xiaoqi Zhang 1,  Xiangqin Fang 1,  Jiqin Lian 6,  Lin Chen 7,  Siru Zhou 8,  Zhenhong Ni 9
Affiliations

Affiliations

  • 1 Department of Rehabilitation Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China.
  • 2 Department of General Medicine, Chinese PLA General Hospital of Central Theater Command, Wuhan, China.
  • 3 Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma and Chemical Poisoning, Trauma Center, Research Institute of Surgery, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China.
  • 4 Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University of PLA, Chongqing, China.
  • 5 Department of Pharmacy and Clinical Laboratory, Army Medical University of PLA, Chongqing, China.
  • 6 Department of Pharmacy and Clinical Laboratory, Army Medical University of PLA, Chongqing, China. lianjiqin@sina.com.
  • 7 Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma and Chemical Poisoning, Trauma Center, Research Institute of Surgery, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China. linchen70@163.com.
  • 8 War Trauma Medical Center, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center, Daping Hospital, Army Medical University, Chongqing, China. zhousiru1025@163.com.
  • 9 Department of Rehabilitation Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China. nizhenhong1986@163.com.
  • # Contributed equally.
PMID: 40579479 DOI: 10.1038/s43587-025-00907-0
Abstract

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.

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