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Sex differences in heart mitochondria regulate diastolic dysfunction

Authors :
Yang Cao
Laurent Vergnes
Yu-Chen Wang
Calvin Pan
Karthickeyan Chella Krishnan
Timothy M. Moore
Manuel Rosa-Garrido
Todd H. Kimball
Zhiqiang Zhou
Sarada Charugundla
Christoph D. Rau
Marcus M. Seldin
Jessica Wang
Yibin Wang
Thomas M. Vondriska
Karen Reue
Aldons J. Lusis
Source :
Nature communications. 13(1)
Publication Year :
2021

Abstract

Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a “two-hit” mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.

Details

ISSN :
20411723
Volume :
13
Issue :
1
Database :
OpenAIRE
Journal :
Nature communications
Accession number :
edsair.doi.dedup.....fa9f21cd0354673d5fba1c6cea765216