Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart-derived extracellular vesicle proteome and induces obesity in female mice

Yow Keat Tham; Bianca C Bernardo; Bethany Claridge; Gunes S Yildiz; Liesel Min-Linn Woon; Simon Bond; Haoyun Fang; Jenny Y Y Ooi; Aya Matsumoto; Jieting Luo; Celeste M K Tai; Claudia A Harmawan; Helen Kiriazis; Daniel G Donner; Natalie A Mellett; E Dale Abel; Sohaib A Khan; David P De Souza; Sheik Nadeem Elahee Doomun; Kevin Liu; Ruidong Xiang; Manika Singh; Michael Inouye; Peter J Meikle; Kate L Weeks; Brian G Drew; David W Greening; Julie R McMullen

doi:10.1038/s44161-023-00223-z

Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart-derived extracellular vesicle proteome and induces obesity in female mice

Nat Cardiovasc Res. 2023 Mar;2(3):268-289. doi: 10.1038/s44161-023-00223-z. Epub 2023 Mar 9.

Authors

Yow Keat Tham^#^{1

2

3}, Bianca C Bernardo^#^{1

3

4}, Bethany Claridge^{1

5

6}, Gunes S Yildiz¹, Liesel Min-Linn Woon¹, Simon Bond^{1

2

3}, Haoyun Fang¹, Jenny Y Y Ooi^{1

2

3}, Aya Matsumoto¹, Jieting Luo¹, Celeste M K Tai¹, Claudia A Harmawan¹, Helen Kiriazis^{1

2}, Daniel G Donner^{1

2}, Natalie A Mellett¹, E Dale Abel⁷, Sohaib A Khan⁸, David P De Souza⁹, Sheik Nadeem Elahee Doomun⁹, Kevin Liu¹, Ruidong Xiang¹, Manika Singh¹, Michael Inouye¹, Peter J Meikle^{1

2

3

6}, Kate L Weeks^{1

2

3

10}, Brian G Drew^{1

2

6

11}, David W Greening^{12

13

14

15

16}, Julie R McMullen^{17

18

19

20

21

22

23}

Affiliations

¹ Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
² Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Victoria, Australia.
³ Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia.
⁴ Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
⁵ Department of Biochemistry and Chemistry, La Trobe University, Melbourne, Victoria, Australia.
⁶ Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia.
⁷ David Geffen School of Medicine, University of California, Los Angeles, California, CA, USA.
⁸ Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁹ Metabolomics Australia, Bio21 Institute, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁰ Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia.
¹¹ Central Clinical School, Monash University, Melbourne, Victoria, Australia.
¹² Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia. [email protected].
¹³ Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Victoria, Australia. [email protected].
¹⁴ Department of Biochemistry and Chemistry, La Trobe University, Melbourne, Victoria, Australia. [email protected].
¹⁵ Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia. [email protected].
¹⁶ Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia. [email protected].
¹⁷ Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia. [email protected].
¹⁸ Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Victoria, Australia. [email protected].
¹⁹ Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia. [email protected].
²⁰ Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia. [email protected].
²¹ Central Clinical School, Monash University, Melbourne, Victoria, Australia. [email protected].
²² Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia. [email protected].
²³ Department of Physiology, Monash University, Melbourne, Victoria, Australia. [email protected].

^# Contributed equally.

PMID: 39196021
DOI: 10.1038/s44161-023-00223-z

Abstract

Dysregulation of estrogen receptor alpha (ERα) has been linked with increased metabolic and cardiovascular disease risk. Here, we generate and characterize cardiomyocyte-specific ERα knockout (ERαHKO) mice to assess the role of ERα in the heart. The most striking phenotype was obesity in female ERαHKO but not male ERαHKO mice. Female ERαHKO mice showed cardiac dysfunction, mild glucose and insulin intolerance and reduced ERα gene expression in skeletal muscle and white adipose tissue. Transcriptomic, proteomic, lipidomic and metabolomic analyses revealed evidence of contractile and/or metabolic dysregulation in heart, skeletal muscle and white adipose tissue. We show that heart-derived extracellular vesicles from female ERαHKO mice contain a distinct proteome associated with lipid and metabolic regulation, and have the capacity to metabolically reprogram the target skeletal myocyte proteome with functional impacts on glycolytic capacity and reserve. This multi-omics study uncovers a cardiac-initiated and sex-specific cardiometabolic phenotype regulated by ERα and provides insights into extracellular vesicle-mediated interorgan communication.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue, White / metabolism
Animals
Disease Models, Animal
Energy Metabolism
Estrogen Receptor alpha* / deficiency
Estrogen Receptor alpha* / genetics
Estrogen Receptor alpha* / metabolism
Extracellular Vesicles* / genetics
Extracellular Vesicles* / metabolism
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout*
Muscle, Skeletal / metabolism
Myocytes, Cardiac* / metabolism
Obesity* / genetics
Obesity* / metabolism
Phenotype
Proteome* / metabolism
Proteomics
Sex Factors

Substances

Estrogen Receptor alpha
Proteome
Esr1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding