Liver‐Secreted Extracellular Vesicles Promote Cirrhosis‐Associated Skeletal Muscle Injury Through mtDNA‐cGAS/STING Axis
Abstract Skeletal muscle atrophy (sarcopenia) is a serious complication of liver cirrhosis, and chronic muscle inflammation plays a pivotal role in its pathologenesis. However, the detailed mechanism through which injured liver tissues mediate skeletal muscle inflammatory injury remains elusive. Her...
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410439 |
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| author | Xiaoli Fan Yunke Peng Bo Li Xiaoze Wang Yifeng Liu Yi Shen Guofeng Liu Yanyi Zheng Qiaoyu Deng Jingping Liu Li Yang |
| author_facet | Xiaoli Fan Yunke Peng Bo Li Xiaoze Wang Yifeng Liu Yi Shen Guofeng Liu Yanyi Zheng Qiaoyu Deng Jingping Liu Li Yang |
| author_sort | Xiaoli Fan |
| collection | DOAJ |
| description | Abstract Skeletal muscle atrophy (sarcopenia) is a serious complication of liver cirrhosis, and chronic muscle inflammation plays a pivotal role in its pathologenesis. However, the detailed mechanism through which injured liver tissues mediate skeletal muscle inflammatory injury remains elusive. Here, it is reported that injured hepatocytes might secrete mtDNA‐enriched extracellular vesicles (EVs) to trigger skeletal muscle inflammation by activating the cGAS‐STING pathway. Briefly, injured liver secreted increased amounts of EVs into circulation, which are then engulfed primarily by macrophages in skeletal muscle and subsequently induce cGAS‐STING signaling and its‐mediated inflammatory response in muscles. In contrast, suppression of hepatic EV secretion or STING signaling significantly alleviated cirrhosis‐induced skeletal muscle inflammation and muscle atrophy in vivo. Circulating EVs from cirrhotic patients showed higher levels of mtDNA, and the levels of EV‐mtDNA positively correlated with the severity of liver injury. In injured hepatocytes, mitochondrial damage promoted the release of cytosolic mtDNA and the subsequent secretion of mtDNA‐enriched EVs. This study reveals that injured hepatocyte‐derived EVs induce skeletal muscle inflammation via the mtDNA‒STING axis, while targeted blockade of liver EV secretion or STING signaling represents a potential therapeutic approach for preventing cirrhosis‐associated skeletal muscle atrophy. |
| format | Article |
| id | doaj-art-5a537fcc9bcc49b0a09802bfbf0bfa6a |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-5a537fcc9bcc49b0a09802bfbf0bfa6a2025-08-20T03:32:24ZengWileyAdvanced Science2198-38442025-03-01129n/an/a10.1002/advs.202410439Liver‐Secreted Extracellular Vesicles Promote Cirrhosis‐Associated Skeletal Muscle Injury Through mtDNA‐cGAS/STING AxisXiaoli Fan0Yunke Peng1Bo Li2Xiaoze Wang3Yifeng Liu4Yi Shen5Guofeng Liu6Yanyi Zheng7Qiaoyu Deng8Jingping Liu9Li Yang10Department of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease West China Hospital Sichuan University Chengdu 610041 ChinaDepartment of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease West China Hospital Sichuan University Chengdu 610041 ChinaDepartment of Radiology West China Hospital Sichuan University Chengdu 610041 ChinaDepartment of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease West China Hospital Sichuan University Chengdu 610041 ChinaDepartment of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease West China Hospital Sichuan University Chengdu 610041 ChinaDepartment of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease West China Hospital Sichuan University Chengdu 610041 ChinaDepartment of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease West China Hospital Sichuan University Chengdu 610041 ChinaDepartment of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease West China Hospital Sichuan University Chengdu 610041 ChinaDepartment of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease West China Hospital Sichuan University Chengdu 610041 ChinaNHC Key Laboratory of Transplant Engineering and Immunology Center for Disease‐related Molecular Network West China Hospital of Sichuan University Chengdu 610041 ChinaDepartment of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease West China Hospital Sichuan University Chengdu 610041 ChinaAbstract Skeletal muscle atrophy (sarcopenia) is a serious complication of liver cirrhosis, and chronic muscle inflammation plays a pivotal role in its pathologenesis. However, the detailed mechanism through which injured liver tissues mediate skeletal muscle inflammatory injury remains elusive. Here, it is reported that injured hepatocytes might secrete mtDNA‐enriched extracellular vesicles (EVs) to trigger skeletal muscle inflammation by activating the cGAS‐STING pathway. Briefly, injured liver secreted increased amounts of EVs into circulation, which are then engulfed primarily by macrophages in skeletal muscle and subsequently induce cGAS‐STING signaling and its‐mediated inflammatory response in muscles. In contrast, suppression of hepatic EV secretion or STING signaling significantly alleviated cirrhosis‐induced skeletal muscle inflammation and muscle atrophy in vivo. Circulating EVs from cirrhotic patients showed higher levels of mtDNA, and the levels of EV‐mtDNA positively correlated with the severity of liver injury. In injured hepatocytes, mitochondrial damage promoted the release of cytosolic mtDNA and the subsequent secretion of mtDNA‐enriched EVs. This study reveals that injured hepatocyte‐derived EVs induce skeletal muscle inflammation via the mtDNA‒STING axis, while targeted blockade of liver EV secretion or STING signaling represents a potential therapeutic approach for preventing cirrhosis‐associated skeletal muscle atrophy.https://doi.org/10.1002/advs.202410439cGAS‐STINGextracellular vesiclesliver fibrosismtDNAskeletal muscle atrophy |
| spellingShingle | Xiaoli Fan Yunke Peng Bo Li Xiaoze Wang Yifeng Liu Yi Shen Guofeng Liu Yanyi Zheng Qiaoyu Deng Jingping Liu Li Yang Liver‐Secreted Extracellular Vesicles Promote Cirrhosis‐Associated Skeletal Muscle Injury Through mtDNA‐cGAS/STING Axis Advanced Science cGAS‐STING extracellular vesicles liver fibrosis mtDNA skeletal muscle atrophy |
| title | Liver‐Secreted Extracellular Vesicles Promote Cirrhosis‐Associated Skeletal Muscle Injury Through mtDNA‐cGAS/STING Axis |
| title_full | Liver‐Secreted Extracellular Vesicles Promote Cirrhosis‐Associated Skeletal Muscle Injury Through mtDNA‐cGAS/STING Axis |
| title_fullStr | Liver‐Secreted Extracellular Vesicles Promote Cirrhosis‐Associated Skeletal Muscle Injury Through mtDNA‐cGAS/STING Axis |
| title_full_unstemmed | Liver‐Secreted Extracellular Vesicles Promote Cirrhosis‐Associated Skeletal Muscle Injury Through mtDNA‐cGAS/STING Axis |
| title_short | Liver‐Secreted Extracellular Vesicles Promote Cirrhosis‐Associated Skeletal Muscle Injury Through mtDNA‐cGAS/STING Axis |
| title_sort | liver secreted extracellular vesicles promote cirrhosis associated skeletal muscle injury through mtdna cgas sting axis |
| topic | cGAS‐STING extracellular vesicles liver fibrosis mtDNA skeletal muscle atrophy |
| url | https://doi.org/10.1002/advs.202410439 |
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