IGF1 Knockdown Hinders Myocardial Development through Energy Metabolism Dysfunction Caused by ROS-Dependent FOXO Activation in the Chicken Heart.

Yafan Gong,Yingying Zheng,Jie Yang,Yuan Zhang,Honggui Liu,Jingzeng Cai,Dahai Yu,Qi Liu,Ziwei Zhang

doi:10.1155/2019/7838754

Abstract

Insulin-like growth factor 1 (IGF1) is a multifunctional cellular regulatory factor that can regulate cell growth and development by mediating growth hormone stimulation. However, the mechanism of IGF1 dysfunction in cardiomyocyte development is seldom reported. To study this, we employed the models of IGF1 knockdown in chicken embryo in vivo and in cardiomyocytes in vitro. We detected the antioxidant capacity, PI3K/Akt pathway, energy metabolism-related genes, and myocardial development-related genes. Our results revealed that the low expression of IGF1 can significantly suppress the antioxidant capacity and increase the ROS (P < 0.05) levels, activating the AMPK and PI3K pathway by inhibiting the expression of IRS1. We also found that myocardial energy metabolism is blocked through IGF1, GLUT, and IGFBP inhibition, further inducing myocardial developmental disorder by inhibiting Mesp1, GATA, Nkx2.5, and MyoD expression. Altogether, we conclude that low IGF1 expression can hinder myocardial development through the dysfunction of energy metabolism caused by ROS-dependent FOXO activation.

Highlights

Insulin-like growth factors (IGFs) are a group of polypeptides with growth-promoting function
We demonstrated that selenium deficiency disrupted insulin responsiveness through inhibition of the phosphatidylinositol 3kinase (PI3K)/Akt pathway by producing excessive oxygen free radicals [19, 20]; selenium deficiency can downregulate the expression of insulin-like growth factor 1 (IGF1)
We examined the effects of IGF1 knockdown on the mRNA abundance of insulinrelated genes (IGF1R, glucose transporter-1 (GLUT1), glucose transporter-3 (GLUT3), glucose transporter-8 (GLUT8), insulin-like growth factor-binding protein-1 (IGFBP1), insulin-like growth factor-binding protein-2 (IGFBP2), insulin-like growth factor-binding protein-3 (IGFBP3), insulin-like growth factor-binding protein-4 (IGFBP4), insulin-like growth factor-binding protein-5 (IGFBP5), insulin-like growth factor-binding protein-7 (IGFBP7), insulin receptor (IR), and insulin receptor substrate-1 (IRS1))

Summary

Introduction

Insulin-like growth factors (IGFs) are a group of polypeptides with growth-promoting function. IGFs play an important role in cell proliferation, differentiation, individual growth, and development [2]. The production of IGF1 is dependent on the growth hormone (GH), which is an important growth factor in life processes. Myocardial development is a complex process that is regulated by complex molecular networks composed of many development-related factors. Many studies have shown that various signal pathways are involved in the development of vertebrate hearts, including the bone morphogenetic protein (BMP), Wnt, Notch, and fibroblast growth factor 4 (FGF 4) signal transduction pathways. The BMP and Wnt signaling pathways play an important role in the development of early mesoderm cells into cardiomyocytes; they act on the cardiac-specific transcription factor GATA4 and Nkx2.5 through a signal cascade process, promoting the differentiation of cardiac precursor cells into cardiomyocytes [3, 4]. Musarò et al demonstrated that localized synthesis of IGF1 is closely related to skeletal muscle hypertrophy, the molecular pathways of which are similar to those responsible for cardiac hypertrophy [5]

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Conclusion