Circ-Ddx60 contributes to the antihypertrophic memory of exercise hypertrophic preconditioning

Authors：Zhu, Yingqi; Zheng, Cankun; Zhang, Rui; Yan, Junyu; Li, Mingjue; Ma, Siyuan; Chen, Kaitong; Chen, Lu; Liu, Jichen; Xiu, Jiancheng; Liao, Wangjun; Bin, Jianping; Huang, Jianhua; Lin, Hairuo; Liao, Yulin^*

Source：Journal of Advanced Research, 2023, 46: 113-121.

DOI：10.1016/j.jare.2022.06.005

• Myocardial hypertrophy
• Exercise hypertrophic preconditioning
• Circular RNA
• Eukaryotic elongation factor 2

Introduction: We previously reported a phenomenon called exercise hypertrophic preconditioning (EHP), the underlying mechanisms of which need further clarification.Objectives: We aimed to investigate whether circular RNAs (circRNAs) are involved in EHP.Methods: CircRNA sequencing of myocardial tissue was performed in male C57BL/6 mice with EHP and sedentary. Bioinformatics analysis and Sanger sequencing were used to screen hub circRNA expression and to detect full-length circRNAs, respectively. Loss-of-function analyses were conducted to assess the effects of circ-Ddx60 (c-Ddx) on EHP. After 21 days of swimming training or resting, mice underwent transverse aortic constriction (TAC) or sham surgery. Echocardiography, invasive hemodynamic measure-ment and histological analysis were used to evaluate cardiac remodeling and function. The presence of interaction between c-Ddx and proteins was investigated using comprehensive identification of RNA -binding proteins by mass spectrometry (ChIRP-MS).Results: In this study, we identified a novel circRNA, named c-Ddx that was preferentially expressed in myocardial tissue and significantly up-regulated in EHP mice. Silencing of c-Ddx attenuated the antihy-pertrophic effect of EHP and worsened heart failure in mice that underwent TAC. ChIRP-MS and molec-ular docking analysis validated the combination of c-Ddx and eukaryotic elongation factor 2 (eEF2). Mechanistically, c-Ddx silencing inhibited the increase of phosphorylation of eEF2 and its upstream AMP-activated protein kinase (AMPK) induced by EHP.Conclusions: C-Ddx contributes to the antihypertrophic memory of EHP by binding and activating eEF2, which would provide opportunity to search new therapeutic targets for pathological hypertrophy of heart.

• Institution
  1; 南方医科大学