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

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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Publication Details

Journal
Nature Aging
Published
2025-06-27
DOI
https://doi.org/10.1038/s43587-025-00907-0
Citations
29
Primary Topic
Circular RNAs in diseases
Type
article
Field-Weighted Citation Impact
23.37
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article

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

Yaran Wu, Bin Zhang, Siru Zhou, Daibo Feng et al.
29 citations
Nature Aging
Circular RNAs in diseases
23.37
article

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

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

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.

Nature AgingVol. 5(7)
Army Medical University (CN), Daping Hospital (CN), Central Hospital of Wuhan (CN), Wuhan General Hospital of Guangzhou (CN), PLA Army Engineering University (CN), Chongqing Medical University (CN)
Zero hunger
Openalex Percentile: Top 0%
Circular RNAs in diseases
23.37
DOIOpen Access PDFOpenAlex
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