A Kinase Interacting Protein 1 (AKIP1) promotes cardiomyocyte elongation and physiological cardiac remodelling

Kirsten T. Nijholt, Pablo I. Sánchez-Aguilera, Harmen G. Booij, Silke U. Oberdorf-Maass, Martin M. Dokter, Anouk H.G. Wolters, Ben N.G. Giepmans, Wiek H. van Gilst, Joan H. Brown, Rudolf A. de Boer, Herman H.W. Silljé, B. Daan Westenbrink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

A Kinase Interacting Protein 1 (AKIP1) is a signalling adaptor that promotes physiological hypertrophy in vitro. The purpose of this study is to determine if AKIP1 promotes physiological cardiomyocyte hypertrophy in vivo. Therefore, adult male mice with cardiomyocyte-specific overexpression of AKIP1 (AKIP1-TG) and wild type (WT) littermates were caged individually for four weeks in the presence or absence of a running wheel. Exercise performance, heart weight to tibia length (HW/TL), MRI, histology, and left ventricular (LV) molecular markers were evaluated. While exercise parameters were comparable between genotypes, exercise-induced cardiac hypertrophy was augmented in AKIP1-TG vs. WT mice as evidenced by an increase in HW/TL by weighing scale and in LV mass on MRI. AKIP1-induced hypertrophy was predominantly determined by an increase in cardiomyocyte length, which was associated with reductions in p90 ribosomal S6 kinase 3 (RSK3), increments of phosphatase 2A catalytic subunit (PP2Ac) and dephosphorylation of serum response factor (SRF). With electron microscopy, we detected clusters of AKIP1 protein in the cardiomyocyte nucleus, which can potentially influence signalosome formation and predispose a switch in transcription upon exercise. Mechanistically, AKIP1 promoted exercise-induced activation of protein kinase B (Akt), downregulation of CCAAT Enhancer Binding Protein Beta (C/EBPβ) and de-repression of Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 4 (CITED4). Concludingly, we identified AKIP1 as a novel regulator of cardiomyocyte elongation and physiological cardiac remodelling with activation of the RSK3-PP2Ac-SRF and Akt-C/EBPβ-CITED4 pathway. These findings suggest that AKIP1 may serve as a nodal point for physiological reprogramming of cardiac remodelling.

Original languageEnglish
Article number4046
JournalScientific Reports
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2023
Externally publishedYes

Bibliographical note

Funding Information:
Dr. Westenbrink is supported by the Netherlands Organisation for Scientific Research (NWO VENI, grant 016.176.147) and the Netherlands Heart Foundation Senior Clinical Scientist Grant (2019T064) and CVON DOUBLE DOSE (grant 2020–8005). Dr. de Boer is supported by the Netherlands Heart Foundation (CVON DOUBLE DOSE, grant 2020–8005, CVON SHE-PREDICTS-HF, grant 2017–21, and CVON RED-CVD, grant 2017–11) and the European Research Council (ERC CoG 818715, SECRETE-HF). Part of the work has been performed in the UMCG Microscopy and Imaging Centre (UMIC), sponsored by ZonMW grant 91111.006; the Netherlands Electron Microscopy Infrastructure (NEMI), NWO National Roadmap for Large-Scale Research Infrastructure of the Dutch Research Council (NWO 184.034.014).

Publisher Copyright:
© 2023, The Author(s).

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