Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine
Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine
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DOI：
10.1152/ajpendo.00330.2013
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发表时间：
2014-03-01
影响因子：
5.1
通讯作者：
Klaus, Susanne
中科院分区：
文献类型：
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作者：
Keipert, Susanne;Ost, Mario;Klaus, Susanne
骨骼肌（SM）中异位表达解偶联蛋白1（UCP 1）的UCP 1-Tg小鼠是改善底物代谢和延长寿命的模型。肌因子表达的分析显示SM中成纤维细胞生长因子21（FGF 21）的诱导，导致UCP 1-Tg小鼠中循环FGF 21升高约5倍。尽管肌肉质量减少，但UCP 1-Tg小鼠没有表现出肌病或肌肉自噬缺陷的证据，而是表现出SM中综合应激反应（ISR; eIF 2 alpha/ATF 4）的激活。通过用解偶联剂FCCP处理C2 C12成肌细胞在体外靶向线粒体功能导致ISR的剂量依赖性激活，这与FGF 21表达增加相关，这也通过用呼吸链抑制剂抗霉素A和粘噻唑处理观察到。FGF 21作用所需的辅因子β- klotho在UCP 1-Tg小鼠的白色脂肪组织（WAT）中表达，其显示WAT的布朗宁增加，类似于改变的脂肪细胞形态、增加的棕色脂肪细胞标志物（UCP 1，CIDEA）、脂解（HSL磷酸化）和呼吸能力。重要的是，用转基因小鼠血清处理原代白色脂肪细胞导致UCP 1表达增加。此外，UCP 1-Tg小鼠通过抑制IGF-I-GH轴显示出身长缩短和骨量减少。我们的结论是，诱导成纤维细胞生长因子21作为一种肌细胞因子耦合到线粒体功能和ISR激活SM的干扰。SM释放的FGF 21具有内分泌效应，导致WAT的布朗宁增加，并且可以解释UCP 1-Tg小鼠的健康代谢表型。这些结果证实了肌肉作为全身代谢的重要内分泌调节器。
UCP1-Tg mice with ectopic expression of uncoupling protein1(UCP1) in skeletal muscle (SM) are a model of improved substrate metabolism and increased longevity. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in approximately fivefold elevated circulating FGF21 in UCP1-Tg mice. Despite a reduced muscle mass, UCP1-Tg mice showed no evidence for a myopathy or muscle autophagy deficiency but an activation of integrated stress response (ISR; eIF2 alpha/ATF4) in SM. Targeting mitochondrial function in vitro by treating C2C12 myoblasts with the uncoupler FCCP resulted in a dose-dependent activation of ISR, which was associated with increased expression of FGF21, which was also observed by treatment with respiratory chain inhibitors antimycin A and myxothiazol. The cofactor required for FGF21 action, beta- klotho, was expressed in white adipose tissue (WAT) of UCP1-Tg mice, which showed an increased browning of WAT similar to what occurred in altered adipocyte morphology, increased brown adipocyte markers (UCP1, CIDEA), lipolysis (HSL phosphorylation), and respiratory capacity. Importantly, treatment of primary white adipocytes with serum of transgenic mice resulted in increased UCP1 expression. Additionally, UCP1-Tg mice showed reduced body length through the suppressed IGF-I-GH axis and decreased bone mass. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. FGF21 released from SM has endocrine effects leading to increased browning of WAT and can explain the healthy metabolic phenotype of UCP1-Tg mice. These results confirm muscle as an important endocrine regulator of whole body metabolism.