A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis

Chao Quan, Qian Du, Min Li, Ruizhen Wang, Qian Ouyang, Shu Su, Sangsang Zhu, Qiaoli Chen, Yang Sheng, Liang Chen, Hong Wang, David G. Campbell, Carol MacKintosh, Zhongzhou Yang, Kunfu Ouyang, Hong Yu Wang () and Shuai Chen ()
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Chao Quan: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Qian Du: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Min Li: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Ruizhen Wang: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Qian Ouyang: Model Animal Research Center, Nanjing University
Shu Su: Model Animal Research Center, Nanjing University
Sangsang Zhu: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Qiaoli Chen: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Yang Sheng: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Liang Chen: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Hong Wang: School of Chemical Biology and Biotechnology, Peking University
David G. Campbell: School of Life Sciences, University of Dundee
Carol MacKintosh: School of Life Sciences, University of Dundee
Zhongzhou Yang: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Kunfu Ouyang: School of Chemical Biology and Biotechnology, Peking University
Hong Yu Wang: Model Animal Research Center, Nanjing University
Shuai Chen: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16116-9

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