A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis
A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis
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PKB-SPEG 信号通路通过调节钙稳态将胰岛素抵抗与糖尿病心肌病联系起来
DOI：
10.1038/s41467-020-16116-9
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发表时间：
2020-05-04
影响因子：
16.6
通讯作者：
Chen, Shuai
中科院分区：
文献类型：
--
作者：
Quan, Chao;Du, Qian;Chen, Shuai
糖尿病性心肌病是糖尿病患者的一种进行性疾病，心肌胰岛素抵抗参与其发病机制尚不完全明确。横纹肌优先表达蛋白激酶（SPEG）有两个激酶结构域，是一个关键的心脏调节因子。我们发现SPEG在胰岛素作用下被蛋白激酶B （PKB）磷酸化Ser2461/Ser2462/ thr2463位点。pkb介导的SPEG磷酸化激活其第二激酶结构域，进而磷酸化肌浆/内质网钙atp酶2a （SERCA2a）并加速钙再摄取到SR。心脏特异性缺失PKBα/β或高脂肪饮食抑制胰岛素诱导的SPEG和SERCA2a磷酸化，延长SR钙的再摄取，并损害心功能。携带aspeg3突变以阻止其被PKB磷酸化的小鼠表现出心功能障碍。重要的是，peg3amutation会损害SERCA2a磷酸化和钙再摄取到sr。总的来说，这些数据表明胰岛素抵抗会损害PKB-SPEG-SERCA2a信号轴，这有助于糖尿病性心肌病的发展。
Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing aSpeg3Amutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, theSpeg3Amutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.