衰老巨噬细胞诱导骨骼肌铁下垂,加速骨关节炎相关肌肉萎缩。

IF 17 Q1 CELL BIOLOGY
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
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引用次数: 0

摘要

关节周围肌肉萎缩是骨关节炎(OA)患者的常见问题,但其原因尚不清楚。在这里,我们证明了股四头肌的慢性炎症与小鼠的OA相吻合,其特征是巨噬细胞的增加,炎症途径的激活和组织血管化。我们发现,在OA进展过程中,巨噬细胞逐渐表现出越来越多的衰老表型,并通过旁分泌诱导铁下垂促进肌肉萎缩。机制上,铁超载诱导的线粒体损伤导致天冬酰胺代谢物减少,通过抑制mTORC1-HMGCR信号通路损害辅酶Q10 (CoQ10)的合成。最终,这个级联增强脂质过氧化并促进骨骼肌细胞的铁下垂。我们发现心脏药物CoQ10可以通过抑制铁下垂来减轻肌肉萎缩,从而减少OA关节的病理损伤。我们的研究结果为OA患者肌肉萎缩的潜在管理提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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CiteScore
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