目标:肌肉减少症,一种普遍的情况,显着影响失代偿期肝硬化(DC)患者的预后。DC伴肌肉减少症患者血清成纤维细胞生长因子21(FGF21)水平明显增高。卫星细胞(SCs)在衰老和癌症诱导的少肌症中起作用。这里,我们研究了FGF21和SCs在DC相关肌少症中的作用以及潜在机制.
方法: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Klothoβ(KLB)敲除小鼠SCs以研讨KLB在FGF21下游的感化。此外,收集DC患者和对照患者的生物样本以验证结果.
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,与骨骼肌质量/骨骼肌指数呈显著负相关。肝脏分泌的FGF21诱导SC功能障碍,导致肌肉减少症。机械上,在DC状态下的FGF21表现出与SC表面上的KLB增强的相互作用,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)途径,阻碍SC增殖和分化,并阻断新的肌管形成以修复萎缩。使用中和抗体中和循环FGF21,腺相关病毒对肝FGF21的敲除,或敲除SCs中的KLB可有效改善或逆转DC相关性肌少症。
结论:肝细胞衍生的FGF21介导肝-肌肉串扰,通过抑制PI3K/Akt途径损害肌肉再生,从而证明了DC相关性肌少症的新治疗策略。
OBJECTIVE: 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.