Abstract
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/Thr2463 by 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 a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation 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.
Highlights
Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms
We show that impaired calcium homeostasis due to cardiac insulin resistance contributes to the development of diabetic cardiomyopathy
We demonstrate that this protein kinase B (PKB) − SPEG signaling nexus is critical for maintenance of cardiac function through regulating sarcoplasmic/ endoplasmic reticulum calcium-ATPase 2a (SERCA2a)-mediated calcium reuptake into the sarcoplasmic reticulum (SR) in cardiomyocytes (Fig. 9b)
Summary
Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. The Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR These data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy. The striated muscle preferentially expressed protein kinase (SPEG) is a member of the MLCK subgroup of CaMK Ser/Thr protein kinase family, and plays a critical role in regulating cardiac development and function[12]. It regulates the cardiomyocyte cytoskeleton in the developing heart, and its deficiency causes dilated cardiomyopathy during embryo development and results in neonatal death in mice[12]. We utilize genetically-modified mouse models and their derived cardiomyocytes to demonstrate that impairment of this PKB−SPEG signaling nexus may contribute to the development of diabetic cardiomyopathy
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