Identification of Potentially Relevant Genes for Excessive Exercise-Induced Pathological Cardiac Hypertrophy in Zebrafish

Zuoqiong Zhou,Ping Zhu,Xiyang Peng,Zhanglin Chen,Changfa Tang,Xiushan Wu,Runkang Zhu,Lan Zheng

doi:10.3389/fphys.2020.565307

Abstract

Exercise-induced cardiac remodeling has aroused public concern for some time, as sudden cardiac death is known to occur in athletes; however, little is known about the underlying mechanism of exercise-induced cardiac injury. In the present study, we established an excessive exercise-induced pathologic cardiac hypertrophy model in zebrafish with increased myocardial fibrosis, myofibril disassembly, mitochondrial degradation, upregulated expression of the pathological hypertrophy marker genes in the heart, contractile impairment, and cardiopulmonary function impairment. High-throughput RNA-seq analysis revealed that the differentially expressed genes were enriched in the regulation of autophagy, protein folding, and degradation, myofibril development, angiogenesis, metabolic reprogramming, and insulin and FoxO signaling pathways. FOXO proteins may be the core mediator of the regulatory network needed to promote the pathological response. Further, PPI network analysis showed that pik3c3, gapdh, fbox32, fzr1, ubox5, lmo7a, kctd7, fbxo9, lonrf1l, fbxl4, nhpb2l1b, nhp2, fbl, hsp90aa1.1, snrpd3l, dhx15, mrto4, ruvbl1, hspa8b, and faub are the hub genes that correlate with the pathogenesis of pathological cardiac hypertrophy. The underlying regulatory pathways and cardiac pressure-responsive molecules identified in the present study will provide valuable insights for the supervision and clinical treatment of pathological cardiac hypertrophy induced by excessive exercise.

Highlights

The most frequent medical cause of death in athletes is sudden cardiac death (SCD), which usually occurs during intensive training (Harmon et al, 2014)
An increase in cardiomyocyte apoptosis, necrosis, autophagic cell death, and fibrosis occur after long-term excessive training, which could induce the shift from physiological cardiac hypertrophy to pathological cardiac hypotrophy (Carraro and Franceschi, 1997; Nakai et al, 2007; Oka and Komuro, 2008)
The muscle fibers and mitochondria were neatly arranged in the cardiomyocytes of the control group, while the muscle fibers and mitochondria of the excessively exercised group were arranged in a disorderly manner, and mitochondrial structural abnormalities and autophagy were observed (Figures 1H,I)

Summary

Introduction

The most frequent medical cause of death in athletes is sudden cardiac death (SCD), which usually occurs during intensive training (Harmon et al, 2014). An increase in cardiomyocyte apoptosis, necrosis, autophagic cell death, and fibrosis occur after long-term excessive training, which could induce the shift from physiological cardiac hypertrophy to pathological cardiac hypotrophy (Carraro and Franceschi, 1997; Nakai et al, 2007; Oka and Komuro, 2008). Some of the physiological activities of cardiomyocytes, including cell fibrosis, protein synthesis, mitochondrial dysfunction, metabolic reprogramming, and angiogenesis, have been implicated in pathological hypertrophy, but the specific molecular mechanism and molecular regulatory network of exerciseinduced pathogenic cardiac hypotrophy remains unclear. Understanding this relationship will enable effective prevention and control of exercise overload and heart injury, and improve the medical supervision of athletes

Objectives

Methods

Results

Conclusion