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

Author

Listed:
  • 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
    Nanjing University)

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.

Suggested Citation

  • 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 Ou, 2020. "A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16116-9
    DOI: 10.1038/s41467-020-16116-9
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    Cited by:

    1. Sangsang Zhu & Chao Quan & Ruizhen Wang & Derong Liang & Shu Su & Ping Rong & Kun Zhou & Xinyu Yang & Qiaoli Chen & Min Li & Qian Du & Jingzi Zhang & Lei Fang & Hong-Yu Wang & Shuai Chen, 2022. "The RalGAPα1–RalA signal module protects cardiac function through regulating calcium homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Iman Lohraseb & Peter McCarthy & Genevieve Secker & Ceilidh Marchant & Jianmin Wu & Naveid Ali & Sharad Kumar & Roger J. Daly & Natasha L. Harvey & Hiroshi Kawabe & Oded Kleifeld & Sophie Wiszniak & Q, 2022. "Global ubiquitinome profiling identifies NEDD4 as a regulator of Profilin 1 and actin remodelling in neural crest cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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