Exercise ameliorates skeletal muscle insulin resistance by modulating GRK4-mediated D1R expression.

IF 6.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Yu Tao, Wenbin Luo, Yue Chen, Caiyu Chen, Shengnan Chen, Xiaoping Li, Ken Chen, Chunyu Zeng
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Abstract

Exercise has been recommended as a nonpharmaceutical therapy to treat insulin resistance (IR). Previous studies showed that dopamine D1-like receptor agonists, such as fenoldopam, could improve peripheral insulin sensitivity, while antipsychotics, which are dopamine receptor antagonists, increased susceptibility to Type 2 diabetes mellitus (T2DM). Meanwhile, exercise has been proved to stimulate dopamine receptors. However, whether the dopamine D1 receptor (D1R) is involved in exercise-mediated amelioration of IR remains unclear. We found that the D1-like receptor antagonist, SCH23390, reduced the effect of exercise on lowering blood glucose and insulin in insulin-resistant mice and inhibited the contraction-induced glucose uptake in C2C12 myotubes. Similarly, the opposite was true for the D1-like receptor agonist, fenoldopam. Furthermore, the expression of D1R was decreased in skeletal muscles from streptozotocin (STZ)- and high-fat intake-induced T2DM mice, accompanied by increased D1R phosphorylation, which was reversed by exercise. A screening study showed that G protein-coupled receptor kinase 4 (GRK4) may be the candidate kinase for the regulation of D1R function, because, in addition to the increased GRK4 expression in skeletal muscles of T2DM mice, GRK4 transgenic T2DM mice exhibited lower insulin sensitivity, accompanied by higher D1R phosphorylation than control mice, whereas the AAV9-shGRK4 mice were much more sensitive to insulin than AAV9-null mice. Mechanistically, the up-regulation of GRK4 expression caused by increased reactive oxygen species (ROS) in IR was ascribed to the enhanced expression of c-Myc, a transcriptional factor of GRK4. Taken together, the present study shows that exercise, via regulation of ROS/c-Myc/GRK4 pathway, ameliorates D1R dysfunction and improves insulin sensitivity.

运动通过调节GRK4介导的D1R表达来改善骨骼肌胰岛素抵抗。
运动已被推荐为治疗胰岛素抵抗(IR)的非药物疗法。先前的研究表明,多巴胺D1样受体激动剂,如非诺多潘,可以改善外周胰岛素敏感性,而抗精神病药物,即多巴胺受体拮抗剂,增加了对2型糖尿病(T2DM)的易感性。同时,运动已被证明能刺激多巴胺受体。然而,多巴胺D1受体(D1R)是否参与运动介导的IR改善仍不清楚。我们发现D1样受体拮抗剂SCH23390降低了运动对胰岛素抵抗小鼠血糖和胰岛素的降低作用,并抑制了收缩诱导的C2C12肌管的葡萄糖摄取。类似地,D1样受体激动剂非诺多泮的情况正好相反。此外,链脲佐菌素(STZ)和高脂肪摄入诱导的T2DM小鼠骨骼肌中D1R的表达降低,同时D1R磷酸化增加,运动可逆转这种情况。一项筛选研究表明,G蛋白偶联受体激酶4(GRK4)可能是调节D1R功能的候选激酶,因为除了GRK4在T2DM小鼠骨骼肌中的表达增加外,GRK4转基因T2DM小鼠表现出比对照小鼠更低的胰岛素敏感性,伴随着更高的D1R磷酸化,而AAV9-shGRK4小鼠比AAV9-null小鼠对胰岛素更敏感。从机制上讲,由IR中活性氧(ROS)增加引起的GRK4表达上调归因于GRK4的转录因子c-Myc的表达增强。总之,本研究表明,运动通过调节ROS/c-Myc/GRK4途径,改善D1R功能障碍并提高胰岛素敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Clinical science
Clinical science 医学-医学:研究与实验
CiteScore
11.40
自引率
0.00%
发文量
189
审稿时长
4-8 weeks
期刊介绍: Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively: Cardiovascular system Cerebrovascular system Gastrointestinal tract and liver Genomic medicine Infection and immunity Inflammation Oncology Metabolism Endocrinology and nutrition Nephrology Circulation Respiratory system Vascular biology Molecular pathology.
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