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.