肌肉减少症是一种常见疾病，它显着影响失代偿性肝硬化 (DC) 患者的预后。患有肌少症的 DC 患者血清成纤维细胞生长因子 21 (FGF21) 水平显着升高。卫星细胞（SC）在衰老和癌症引起的肌少症中发挥着重要作用。在此，我们研究了FGF21和SCs在DC相关肌少症中的作用及其潜在机制。我们开发了两种DC小鼠模型并进行了体内和体外实验。构建 SC 中的 Klotho beta (KLB) 敲除小鼠以研究 KLB 在 FGF21 下游的作用。此外，还从 DC 患者和对照患者身上采集生物样本来验证结果。在 DC 小鼠模型和 DC 患者中观察到肌肉萎缩和 SC 肌生成受损。观察到肝源性 FGF21 的循环水平升高，其与骨骼肌质量/骨骼肌指数显着负相关。肝脏分泌的 FGF21 会诱导 SC 功能障碍，导致肌肉减少症。从机制上讲，DC 状态下的 FGF21 与 SC 表面上的 KLB 的相互作用增强，导致下游磷酸酶和张力蛋白同源物上调。这会抑制蛋白激酶 B (PI3K/Akt) 通路，阻碍 SC 增殖和分化，并阻止新肌管形成以修复萎缩。使用中和抗体中和循环 FGF21、通过腺相关病毒敲低肝 FGF21 或敲除 SC 中的 KLB，可有效改善或逆转 DC 相关的肌少症。肝细胞源性 FGF21 介导肝肌肉串扰，从而通过抑制PI3K/Akt 通路，从而展示了 DC 相关肌少症的新型治疗策略。版权所有 © 2024。由 Elsevier B.V. 出版。

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.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.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.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.Copyright © 2024. Published by Elsevier B.V.