Liver-secreted FGF21 induces sarcopenia by inhibiting satellite cell myogenesis via klotho beta in decompensated cirrhosis
Da Zhou,
Yifan Shi,
Donghua Zhang,
Junbo Zuo,
Chenghao Zeng,
Gulsudum Mamtawla,
LongChang Huang,
Xuejin Gao,
Li Zhang,
Xinying Wang
Affiliations
Da Zhou
Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China
Yifan Shi
Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China
Donghua Zhang
Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China
Junbo Zuo
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
Chenghao Zeng
Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China
Gulsudum Mamtawla
Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China
LongChang Huang
Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China
Xuejin Gao
Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China
Li Zhang
Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China
Xinying Wang
Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China; Corresponding author. Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, China.
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.
