GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting.
GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting.
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DOI：
10.3390/biomedicines11071909
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发表时间：
2023-07-06
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
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终末期肝病患者表现出进行性骨骼肌萎缩，突出了受损肝脏和肌肉之间的负面串扰。我们的研究是为了确定TGFβ配体是否作为介质发挥作用。四氯化碳单次或多次给药引起急性或慢性肝损伤。肌肉注射心脏毒素诱导骨骼肌损伤和修复。激活素IIB型受体（ActRIIB）配体和生长分化因子8（Gdf 8）分别用ActRIIB-Fc融合蛋白和Gdf 8特异性抗体中和。我们发现，急性肝损伤诱导快速和不良反应的肌肉，这是钝化的中和ActRIIB配体。慢性肝损伤引起肌肉萎缩和修复缺陷，其通过灭活ActRIIB配体来预防或逆转。此外，我们发现，在损伤的小鼠肝脏和缺血的人肝脏中，中心周围肝细胞产生过量的Gdf 8。Gdf 8的特异性失活防止肝损伤诱导的肌肉萎缩，类似于ActRIIB配体的中和。在慢性肝损伤后的治疗范例中，Gdf 8的抑制也逆转了肌肉萎缩。将外源性Gdf 8蛋白直接注射到肌肉中沿着急性局灶性肌肉损伤，重现了与在肝损伤中观察到的类似的失调的肌肉再生。结果表明，受损的肝脏主要通过Gdf 8与肌肉进行负性交流。出乎意料的是，Gdf 8的失活同时改善了慢性肝损伤小鼠的肝纤维化。在体外，Gdf 8诱导人肝星状细胞（LX-2）形成隔样结构，并刺激促纤维化因子的表达。我们的研究结果确定Gdf 8作为一种新的肝肌细胞因子，它与肝损伤进展中的损伤肝-肌肉负串扰沿着。
Patients with end-stage liver disease exhibit progressive skeletal muscle atrophy, highlighting a negative crosstalk between the injured liver and muscle. Our study was to determine whether TGFβ ligands function as the mediators. Acute or chronic liver injury was induced by a single or repeated administration of carbon tetrachloride. Skeletal muscle injury and repair was induced by intramuscular injection of cardiotoxin. Activin type IIB receptor (ActRIIB) ligands and growth differentiation factor 8 (Gdf8) were neutralized with ActRIIB-Fc fusion protein and a Gdf8-specific antibody, respectively. We found that acute hepatic injury induced rapid and adverse responses in muscle, which was blunted by neutralizing ActRIIB ligands. Chronic liver injury caused muscle atrophy and repair defects, which were prevented or reversed by inactivating ActRIIB ligands. Furthermore, we found that pericentral hepatocytes produce excessive Gdf8 in injured mouse liver and cirrhotic human liver. Specific inactivation of Gdf8 prevented liver injury-induced muscle atrophy, similar to neutralization of ActRIIB ligands. Inhibition of Gdf8 also reversed muscle atrophy in a treatment paradigm following chronic liver injury. Direct injection of exogenous Gdf8 protein into muscle along with acute focal muscle injury recapitulated similar dysregulated muscle regeneration as that observed with liver injury. The results indicate that injured liver negatively communicate with the muscle largely via Gdf8. Unexpectedly, inactivation of Gdf8 simultaneously ameliorated liver fibrosis in mice following chronic liver injury. In vitro, Gdf8 induced human hepatic stellate (LX-2) cells to form a septa-like structure and stimulated expression of profibrotic factors. Our findings identified Gdf8 as a novel hepatomyokine contributing to injured liver–muscle negative crosstalk along with liver injury progression.
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作者：
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影响因子：
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期刊：
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