The exercise-inducible bile acid receptor Tgr5 improves skeletal muscle function in mice
The exercise-inducible bile acid receptor Tgr5 improves skeletal muscle function in mice
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DOI：
10.1074/jbc.ra118.002733
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发表时间：
2018-06-29
影响因子：
4.8
通讯作者：
Sato, Ryuichiro
中科院分区：
文献类型：
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作者：
Sasaki, Takashi;Kuboyama, Ayane;Sato, Ryuichiro
TGR 5（也称为G蛋白偶联胆汁酸受体1，GPBAR 1）是一种在许多不同组织中表达的G蛋白偶联胆汁酸受体。TGR 5参与各种代谢过程，包括葡萄糖代谢和能量消耗;然而，TGR 5在骨骼肌中的功能尚未完全了解。使用获得和丧失功能的小鼠模型，我们在这里证明，Tgr 5激活促进肌肉细胞分化和肌肉肥大。具有肌肉特异性Tgr 5表达的年轻和年老转基因小鼠都表现出肌肉力量增加。此外，我们发现，Tgr 5的表达增加的未折叠蛋白反应（UPR），这是一个适应性反应所需的维持内质网（ER）的稳态。内质网应激反应元件（ERSE）和未折叠蛋白反应元件（UPRE）样位点都存在于Tgr 5基因启动子的上游区域，并且对于由Atf 6（激活转录因子6）（一种众所周知的UPR激活的转录调节因子）表达Tgr 5是必需的。我们观察到，在小鼠的骨骼肌中，运动诱导的UPR增加了Tgr 5的表达，这种作用在Atf 6 KO小鼠中被废除，表明Atf 6对这种反应至关重要。这些发现表明，胆汁酸受体Tgr 5有助于改善肌肉功能，并为运动对骨骼肌活性的有益作用提供了额外的解释。
TGR5 (also known as G protein-coupled bile acid receptor 1, GPBAR1) is a G protein-coupled bile acid receptor that is expressed in many diverse tissues. TGR5 is involved in various metabolic processes, including glucose metabolism and energy expenditure; however, TGR5's function in skeletal muscle is not fully understood. Using both gain- and loss-of-function mouse models, we demonstrate here that Tgr5 activation promotes muscle cell differentiation and muscle hypertrophy. Both young and old transgenic mice with muscle-specific Tgr5 expression exhibited increased muscle strength. Moreover, we found that Tgr5 expression is increased by the unfolded protein response (UPR), which is an adaptive response required for maintenance of endoplasmic reticulum (ER) homeostasis. Both ER stress response element (ERSE)- and unfolded protein response element (UPRE)-like sites are present in the 5 upstream region of the Tgr5 gene promoter and are essential for Tgr5 expression by Atf6 (activating transcription factor 6), a well known UPR-activated transcriptional regulator. We observed that in the skeletal muscle of mice, exercise-induced UPR increases Tgr5 expression, an effect that was abrogated in Atf6 KO mice, indicating that Atf6 is essential for this response. These findings indicate that the bile acid receptor Tgr5 contributes to improved muscle function and provide an additional explanation for the beneficial effects of exercise on skeletal muscle activity.