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Vanitha V Rao Sangaiah Umamaheswari Kavitha ArokiaMary Kazufumi Matsushita Shizuo Akira Abhishek Mohanty

Abstract

ABSTRACT


Akirin1 is a small ubiquitously expressed protein, which belongs to a family of highly conserved nuclear proteins called akirins. Due to its nuclear localization and propensity to interact with other proteins, Akirin1 is speculated to regulate transcription of its target genes as a cofactor. Previous studies have shown that Akirin1 is a downstream target of myostatin, which is a negative regulator of myogenesis. Akirin1 was expressed at higher levels in mice lacking myostatin and consistent over-expression of Akirin1 induced hypertrophy in C2C12 myotubes in vitro. While Akirin1 has been mainly studied in skeletal muscle, its role in other muscle tissue remains largely unknown. Here, we studied the function of Akirin1 specifically in cardiac muscle using Akirin1 knock-out mice as a model system. The results of this study show a novel function of Akirin1 in cardiac muscle. Through histological analysis, we first show that Akirin1 knock-out mice display larger ventricular cavities in the heart as usually seen in left ventricular hypertrophy (LVH). Compared to wild-type, Akirin1 knock-out cardiac muscle showed post-transcriptional up-regulation of serum response factor (SRF), a critical molecule known to maintain the cardiac muscle homeostasis. Consistently, Akirin1 knock-out cardiac muscle displayed transcriptional down-regulation of miR-1 and thus up-regulation of its target genes i.e. β-MyHC and ANP. Finally, ablation of Akirin1 also resulted in the activation of signaling molecules involved in IGF-1/Akt/mTOR pathway that is implicated in increased protein synthesis, all suggestive of cardiac hypertrophy phenotype. Overall, we propose a novel role of Akirin1 in cardiac muscle homeostasis via regulation of SRF and miR-1 expression

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