Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China.
Department of General Surgery, The Affiliated Jinling Hospital of Nanjing Medical University, Nanjing, 210002, China; Department of General Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 210002, China.
Redox Biol. 2024 Oct;76:103333. doi: 10.1016/j.redox.2024.103333. Epub 2024 Aug 30.
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.
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.
肌肉减少症是一种常见病症，显著影响失代偿期肝硬化（DC）患者的预后。患有肌肉减少症的 DC 患者血清成纤维细胞生长因子 21（FGF21）水平显著升高。卫星细胞（SCs）在衰老和癌症引起的肌肉减少症中发挥作用。在此，我们研究了 FGF21 和 SCs 在与 DC 相关的肌肉减少症中的作用及其潜在机制。
我们构建了两种 DC 小鼠模型，并进行了体内和体外实验。构建了 SC 中 Klotho beta（KLB）敲除小鼠，以研究 FGF21 下游的 KLB 作用。此外，从 DC 患者和对照患者中收集生物样本以验证结果。
在 DC 小鼠模型和 DC 患者中观察到肌肉减少和 SC 成肌作用受损。循环中肝源性 FGF21 水平升高，与骨骼肌质量/骨骼肌指数显著负相关。肝脏分泌的 FGF21 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 相互作用增强，导致下游磷酸酶和张力蛋白同源物上调。这抑制了蛋白激酶 B（PI3K/Akt）通路，阻碍了 SC 的增殖和分化，并阻止新的肌管形成以修复萎缩。使用中和抗体中和循环 FGF21、腺相关病毒敲低肝 FGF21 或在 SC 中敲除 KLB 可有效改善或逆转与 DC 相关的肌肉减少症。
肝细胞衍生的 FGF21 介导肝-肌肉串扰，通过抑制 PI3K/Akt 通路损害肌肉再生，为与 DC 相关的肌肉减少症提供了一种新的治疗策略。
