Novel circRNA-miRNA-mRNA networks regulated by maternal exercise in fetal hearts of pregestational diabetes

Fang Ye; Xiangru Lu; Ryleigh van Neck; Douglas L Jones; Qingping Feng

doi:10.1016/j.lfs.2022.121308

Novel circRNA-miRNA-mRNA networks regulated by maternal exercise in fetal hearts of pregestational diabetes

Life Sci. 2023 Feb 1:314:121308. doi: 10.1016/j.lfs.2022.121308. Epub 2022 Dec 21.

Authors

Fang Ye¹, Xiangru Lu², Ryleigh van Neck², Douglas L Jones³, Qingping Feng⁴

Affiliations

¹ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Health Science Center, East China Normal University, Shanghai, China.
² Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
³ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Division of Cardiology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada.
⁴ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Division of Cardiology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada. Electronic address: qfeng@uwo.ca.

PMID: 36563841
DOI: 10.1016/j.lfs.2022.121308

Abstract

Background: Maternal exercise lowers the incidence of congenital heart defects (CHDs) induced by pregestational diabetes. However, the molecular mechanisms underlying the beneficial effects of maternal exercise remain unclear. The present study aimed to identify circular RNA (circRNA), microRNA (miRNA) and mRNA networks that are regulated by maternal exercise in fetal hearts of pregestational diabetes.

Methods: Pregestational diabetes was induced in adult C57BL/6 female mice by streptozotocin. The expression profiles of circRNAs, miRNAs and mRNAs in E10.5 fetal hearts of offspring of control and diabetic mothers with or without exercise were analyzed using next generation sequencing. circRNA-miRNA-mRNA networks in fetal hearts were mapped and key candidate transcripts were verified by qPCR analysis.

Results: Pregestational diabetes dysregulated the expression of 206 circRNAs, 66 miRNAs and 391 mRNAs in fetal hearts. Maternal exercise differentially regulated 188 circRNAs, 57 miRNAs and 506 mRNAs in fetal hearts of offspring of pregestational diabetes. A total of 5 circRNAs, 12 miRNAs, and 28 mRNAs were incorporated into a final maternal exercise-associated regulatory network in fetal hearts of offspring of maternal diabetes. Notably, maternal exercise normalized the dysregulated circ_0003226/circ_0015638/miR-351-5p and circ_0002768/miR-3102-3p.2-3p pairs in fetal hearts of pregestational diabetes.

Conclusion: Maternal exercise reverses the dysregulated circ_0003226/circ_0015638/miR-351-5p and circ_0002768/miR-3102-3p.2-3p pairs, and partially normalizes circRNA, miRNA, and mRNA expression profiles in fetal hearts of pregestational diabetes. These findings shed new light on the potential mechanisms of the beneficial effects of maternal exercise on the developing heart in diabetic pregnancies.

Keywords: Maternal exercise; Pregestational diabetes; RNA sequencing; circRNA-associated network; miRNA.

MeSH terms

Animals
Diabetes, Gestational* / genetics
Female
Fetal Heart / metabolism
Gene Regulatory Networks
Humans
Mice
Mice, Inbred C57BL
MicroRNAs* / genetics
Pregnancy
RNA, Circular / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

MicroRNAs
RNA, Circular
RNA, Messenger