Sarcoplasmic reticulum Ca2+ ATPase pump is a major regulator of glucose transport in the healthy and diabetic heart.
Sarcoplasmic reticulum Ca2+ ATPase pump is a major regulator of glucose transport in the healthy and diabetic heart.
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DOI：
10.1016/j.bbadis.2015.01.009
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发表时间：
2015-05
期刊：
影响因子：
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通讯作者：
A. Waller;A. Kalyanasundaram;S. Hayes;M. Periasamy;V. Lacombe
中科院分区：
文献类型：
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作者：
A. Waller;A. Kalyanasundaram;S. Hayes;M. Periasamy;V. Lacombe
尽管深入研究，介导钙（Ca2 +）刺激的横纹肌葡萄糖运输的途径仍然难以捉摸。由于肌浆网钙atp酶（SERCA）泵紧密调节细胞质[Ca2 +]，我们研究了SERCA泵是否是心脏葡萄糖运输的主要调节剂。我们使用在心脏中表达SERCA1a的健康和胰岛素缺乏的糖尿病转基因（TG）小鼠。用生物素化光标记法测定完整灌注心肌和离体肌细胞中活性细胞表面葡萄糖转运蛋白(GLUT)-4的含量。在健康的TG小鼠中，心脏特异性SERCA1a表达增加了活跃的细胞表面GLUT4和心肌中的葡萄糖摄取，以及全身葡萄糖耐量。糖尿病降低了野生型小鼠心脏的活性细胞表面GLUT4含量和葡萄糖摄取，所有这些在糖尿病TG小鼠中都被保留了下来。基础AS160的降低和钙调素结合AS160比例的增加与TG小鼠心脏细胞表面GLUT4含量的增加平行，表明AS160通过Ca2 +/钙调素依赖途径调节GLUT运输。此外，心脏特异性SERCA1a表达可部分缓解糖尿病期间的高血糖。总的来说，这些数据表明，在健康和胰岛素缺乏状态下，SERCA泵是通过AS160依赖机制调节心脏葡萄糖运输的主要调节因子。我们的数据进一步表明，心脏特异性SERCA过表达可挽救糖尿病诱导的心脏葡萄糖转运改变，并改善全身葡萄糖稳态。因此，本研究的发现提供了新的机制见解，将心脏SERCA泵的上调作为改善糖尿病期间葡萄糖代谢的潜在治疗靶点。
Despite intensive research, the pathways that mediate calcium (Ca2 +)-stimulated glucose transport in striated muscle remain elusive. Since the sarcoplasmic reticulum calcium ATPase (SERCA) pump tightly regulates cytosolic [Ca2 +], we investigated whether the SERCA pump is a major regulator of cardiac glucose transport. We used healthy and insulin-deficient diabetic transgenic (TG) mice expressing SERCA1a in the heart. Active cell surface glucose transporter (GLUT)-4 was measured by a biotinylated photolabeled assay in the intact perfused myocardium and isolated myocytes. In healthy TG mice, cardiac-specific SERCA1a expression increased active cell-surface GLUT4 and glucose uptake in the myocardium, as well as whole body glucose tolerance. Diabetes reduced active cell-surface GLUT4 content and glucose uptake in the heart of wild type mice, all of which were preserved in diabetic TG mice. Decreased basal AS160 and increased proportion of calmodulin-bound AS160 paralleled the increase in cell surface GLUT4 content in the heart of TG mice, suggesting that AS160 regulates GLUT trafficking by a Ca2 +/calmodulin dependent pathway. In addition, cardiac-specific SERCA1a expression partially rescues hyperglycemia during diabetes. Collectively, these data suggested that the SERCA pump is a major regulator of cardiac glucose transport by an AS160 dependent mechanism during healthy and insulin-deficient state. Our data further indicated that cardiac-specific SERCA overexpression rescues diabetes induced-alterations in cardiac glucose transport and improves whole body glucose homeostasis. Therefore, findings from this study provide novel mechanistic insights linking upregulation of the SERCA pump in the heart as a potential therapeutic target to improve glucose metabolism during diabetes.