Da Zhou , Yifan Shi , Donghua Zhang , Junbo Zuo , Chenghao Zeng , Gulsudum Mamtawla , LongChang Huang , Xuejin Gao , Li Zhang , Xinying Wang
{"title":"肝脏分泌的 FGF21 通过 klotho beta 抑制失代偿期肝硬化患者的卫星细胞肌生成，从而诱发肌肉疏松症","authors":"Da Zhou , Yifan Shi , Donghua Zhang , Junbo Zuo , Chenghao Zeng , Gulsudum Mamtawla , LongChang Huang , Xuejin Gao , Li Zhang , Xinying Wang","doi":"10.1016/j.redox.2024.103333","DOIUrl":null,"url":null,"abstract":"<div><h3>Background & aims</h3><p>Sarcopenia, a prevalent condition, significantly impacts the prognosis of patients with decompensated cirrhosis (DC). Serum fibroblast growth factor 21 (FGF21) levels are significantly higher in DC patients with sarcopenia. Satellite cells (SCs) play a role in aging- and cancer-induced sarcopenia. Here, we investigated the roles of FGF21 and SCs in DC-related sarcopenia as well as the underlying mechanisms.</p></div><div><h3>Methods</h3><p>We developed two DC mouse models and performed in vivo and in vitro experiments. Klotho beta (KLB) knockout mice in SCs were constructed to investigate the role of KLB downstream of FGF21. In addition, biological samples were collected from patients with DC and control patients to validate the results.</p></div><div><h3>Results</h3><p>Muscle wasting and impaired SC myogenesis were observed in the DC mouse model and patients with DC. Elevated circulating levels of liver-derived FGF21 were observed, which were significantly negatively correlated with skeletal muscle mass/skeletal muscle index. Liver-secreted FGF21 induces SC dysfunction, contributing to sarcopenia. Mechanistically, FGF21 in the DC state exhibits enhanced interactions with KLB on SC surfaces, leading to downstream phosphatase and tensin homolog upregulation. This inhibits the protein kinase B (PI3K/Akt) pathway, hampering SC proliferation and differentiation, and blocking new myotube formation to repair atrophy. Neutralizing circulating FGF21 using neutralizing antibodies, knockdown of hepatic FGF21 by adeno-associated virus, or knockout of KLB in SCs effectively improved or reversed DC-related sarcopenia.</p></div><div><h3>Conclusions</h3><p>Hepatocyte-derived FGF21 mediates liver-muscle crosstalk, which impairs muscle regeneration via the inhibition of the PI3K/Akt pathway, thereby demonstrating a novel therapeutic strategy for DC-related sarcopenia.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"76 ","pages":"Article 103333"},"PeriodicalIF":10.7000,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003112/pdfft?md5=dc6982b977379b43cd22cebf1547c570&pid=1-s2.0-S2213231724003112-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Liver-secreted FGF21 induces sarcopenia by inhibiting satellite cell myogenesis via klotho beta in decompensated cirrhosis\",\"authors\":\"Da Zhou , Yifan Shi , Donghua Zhang , Junbo Zuo , Chenghao Zeng , Gulsudum Mamtawla , LongChang Huang , Xuejin Gao , Li Zhang , Xinying Wang\",\"doi\":\"10.1016/j.redox.2024.103333\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background & aims</h3><p>Sarcopenia, a prevalent condition, significantly impacts the prognosis of patients with decompensated cirrhosis (DC). Serum fibroblast growth factor 21 (FGF21) levels are significantly higher in DC patients with sarcopenia. Satellite cells (SCs) play a role in aging- and cancer-induced sarcopenia. Here, we investigated the roles of FGF21 and SCs in DC-related sarcopenia as well as the underlying mechanisms.</p></div><div><h3>Methods</h3><p>We developed two DC mouse models and performed in vivo and in vitro experiments. Klotho beta (KLB) knockout mice in SCs were constructed to investigate the role of KLB downstream of FGF21. In addition, biological samples were collected from patients with DC and control patients to validate the results.</p></div><div><h3>Results</h3><p>Muscle wasting and impaired SC myogenesis were observed in the DC mouse model and patients with DC. Elevated circulating levels of liver-derived FGF21 were observed, which were significantly negatively correlated with skeletal muscle mass/skeletal muscle index. Liver-secreted FGF21 induces SC dysfunction, contributing to sarcopenia. Mechanistically, FGF21 in the DC state exhibits enhanced interactions with KLB on SC surfaces, leading to downstream phosphatase and tensin homolog upregulation. This inhibits the protein kinase B (PI3K/Akt) pathway, hampering SC proliferation and differentiation, and blocking new myotube formation to repair atrophy. Neutralizing circulating FGF21 using neutralizing antibodies, knockdown of hepatic FGF21 by adeno-associated virus, or knockout of KLB in SCs effectively improved or reversed DC-related sarcopenia.</p></div><div><h3>Conclusions</h3><p>Hepatocyte-derived FGF21 mediates liver-muscle crosstalk, which impairs muscle regeneration via the inhibition of the PI3K/Akt pathway, thereby demonstrating a novel therapeutic strategy for DC-related sarcopenia.</p></div>\",\"PeriodicalId\":20998,\"journal\":{\"name\":\"Redox Biology\",\"volume\":\"76 \",\"pages\":\"Article 103333\"},\"PeriodicalIF\":10.7000,\"publicationDate\":\"2024-08-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2213231724003112/pdfft?md5=dc6982b977379b43cd22cebf1547c570&pid=1-s2.0-S2213231724003112-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Redox Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2213231724003112\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Redox Biology","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2213231724003112","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Liver-secreted FGF21 induces sarcopenia by inhibiting satellite cell myogenesis via klotho beta in decompensated cirrhosis
Background & aims
Sarcopenia, a prevalent condition, significantly impacts the prognosis of patients with decompensated cirrhosis (DC). Serum fibroblast growth factor 21 (FGF21) levels are significantly higher in DC patients with sarcopenia. Satellite cells (SCs) play a role in aging- and cancer-induced sarcopenia. Here, we investigated the roles of FGF21 and SCs in DC-related sarcopenia as well as the underlying mechanisms.
Methods
We developed two DC mouse models and performed in vivo and in vitro experiments. Klotho beta (KLB) knockout mice in SCs were constructed to investigate the role of KLB downstream of FGF21. In addition, biological samples were collected from patients with DC and control patients to validate the results.
Results
Muscle wasting and impaired SC myogenesis were observed in the DC mouse model and patients with DC. Elevated circulating levels of liver-derived FGF21 were observed, which were significantly negatively correlated with skeletal muscle mass/skeletal muscle index. Liver-secreted FGF21 induces SC dysfunction, contributing to sarcopenia. Mechanistically, FGF21 in the DC state exhibits enhanced interactions with KLB on SC surfaces, leading to downstream phosphatase and tensin homolog upregulation. This inhibits the protein kinase B (PI3K/Akt) pathway, hampering SC proliferation and differentiation, and blocking new myotube formation to repair atrophy. Neutralizing circulating FGF21 using neutralizing antibodies, knockdown of hepatic FGF21 by adeno-associated virus, or knockout of KLB in SCs effectively improved or reversed DC-related sarcopenia.
Conclusions
Hepatocyte-derived FGF21 mediates liver-muscle crosstalk, which impairs muscle regeneration via the inhibition of the PI3K/Akt pathway, thereby demonstrating a novel therapeutic strategy for DC-related sarcopenia.
期刊介绍：
Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease.
Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.
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