Formononetin ameliorates muscle atrophy by regulating myostatin-mediated PI3K/Akt/FoxO3a pathway and satellite cell function in chronic kidney disease.
Formononetin ameliorates muscle atrophy by regulating myostatin-mediated PI3K/Akt/FoxO3a pathway and satellite cell function in chronic kidney disease.
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芒柄花素通过调节慢性肾脏病中肌生长抑制素介导的 PI3K/Akt/FoxO3a 通路和卫星细胞功能来改善肌肉萎缩
DOI：
10.1111/jcmm.16238
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发表时间：
2021-03
影响因子：
5.3
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Liu L;Hu R;You H;Li J;Liu Y;Li Q;Wu X;Huang J;Cai X;Wang M;Wei L
肌肉萎缩是慢性肾脏病(CKD)的常见并发症。炎症和肌肉抑制素在CKD肌萎缩中起重要作用。芒柄花素(Formononetin，FMN)是黄芪中主要的生物活性异黄酮类化合物，具有抗炎和促进肌细胞分化的作用。本研究以肌肉生长抑制素为基础，探讨FMN在CKD肌萎缩中的作用及机制。本研究采用慢性肾脏病大鼠和肿瘤坏死因子α诱导的C2C12肌管作为体内和体外肌肉萎缩模型。结果表明，FMN能显著改善CKD大鼠的肾功能、营养状况和炎症指标。FMN组大鼠的体重、胫前肌和腓肠肌的重量以及骨骼肌的横截面积(CSA)均显著大于对照组。此外，FMN还能显著抑制CKD大鼠肌肉和肿瘤坏死因子-α诱导的C2C12肌管中MURF-1、MAFbx和Myostatin的表达。重要的是，FMN显著增加CKD大鼠肌肉和C2C12肌管中PI3K、Akt和FOXO3a的磷酸化，以及成肌增殖和分化标志物、成肌分化因子D(MyoD)和肌生成素的表达。在肿瘤坏死因子-α诱导的C2C12肌管中也观察到了类似的结果。值得注意的是，myostatin过表达质粒(Myostatin OE)阻断了FMN对PI3K/Akt/FOXO3a通路的磷酸化以及MyoD和mygenin表达的影响。我们的研究结果表明，FMN改善了与肌肉抑制素介导的PI3K/Akt/FOXO3a通路和卫星细胞功能有关的肌肉萎缩。
Muscle atrophy is a common complication in chronic kidney disease (CKD). Inflammation and myostatin play important roles in CKD muscle atrophy. Formononetin (FMN), which is a major bioactive isoflavone compound in Astragalus membranaceus, exerts anti‐inflammatory effects and the promotion of myogenic differentiation. Our study is based on myostatin to explore the effects and mechanisms of FMN in relation to CKD muscle atrophy. In this study, CKD rats and tumour necrosis factor α (TNF‐α)‐induced C2C12 myotubes were used for in vivo and in vitro models of muscle atrophy. The results showed that FMN significantly improved the renal function, nutritional status and inflammatory markers in CKD rats. Values for bodyweight, weight of tibialis anterior and gastrocnemius muscles, and cross‐sectional area (CSA) of skeletal muscles were significantly larger in the FMN treatment rats. Furthermore, FMN significantly suppressed the expressions of MuRF‐1, MAFbx and myostatin in the muscles of CKD rats and the TNF‐α‐induced C2C12 myotubes. Importantly, FMN significantly increased the phosphorylation of PI3K, Akt, and FoxO3a and the expressions of the myogenic proliferation and differentiation markers, myogenic differentiation factor D (MyoD) and myogenin in muscles of CKD rats and the C2C12 myotubes. Similar results were observed in TNF‐α‐induced C2C12 myotubes transfected with myostatin‐small interfering RNA (si‐myostatin). Notably, myostatin overexpression plasmid (myostatin OE) abolished the effect of FMN on the phosphorylation of the PI3K/Akt/FoxO3a pathway and the expressions of MyoD and myogenin. Our findings suggest that FMN ameliorates muscle atrophy related to myostatin‐mediated PI3K/Akt/FoxO3a pathway and satellite cell function.
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