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PreprintCited by 31Genetics, Aging, and Longevity in Model OrganismsRNA Research and SplicingAdvanced Proteomics Techniques and Applications

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Proteogenomic characterization of age and sex interactions in cardiac gene expression

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Han, Yu, Wennersten, Sara A., Wright, Julianna, Ludwig, R. W., Lau, Edward, Lam, Maggie P. Y.·2022·American Journal of Physiology-Heart and Circulatory Physiology
DOI 10.1101/2022.05.11.491401PMC PMC9448281

Preprint — published as 10.1152/ajpheart.00244.2022 · Paper page

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Abstract

The risks of heart diseases are significantly modulated by biological age and sex, but how these factors influence baseline cardiac gene expression remains incompletely understood. Here we characterized young adult and early aging mouse hearts using proteogenomics to identify age and sex dependent gene expression signatures in the mouse heart. RNA sequencing from 4 months old and 20 months old female and male C57BL/6J hearts identified thousands of genes with differential transcript abundances both between sexes (male vs. female) and across age groups (20 mo. vs. 4 mo.). Sex-associated cardiac genes are broadly distributed, functioning in the TCA cycle, mitochondrial translation, autophagy, and other processes. In addition, we found over 800 genes with differential aging response between male and female, which are enriched in calmodulin signaling and cell cycle regulations. Comparison with mass spectrometry data shows a cluster of metabolism genes with up-regulated transcripts but down-regulated protein levels in aging hearts, consistent with an uncoupling of transcriptional regulations in the genetic program with protein compositions. An analysis of sex-adjusted aging cardiac transcriptomes further revealed widespread remodeling of exon usage patterns that is largely independent from differential gene expression, concomitant with upstream changes in RNA-binding protein and splice factor transcripts. To evaluate the potential impact of the splicing events on proteoform composition in the heart, we applied an RNA-guided-proteomics computational pipeline to analyze the mass spectrometry data, and putatively identified hundreds of splice events with the potential to rewire the cardiac proteome through producing detectable splice isoform specific peptides. Taken together, this study contributes to emerging evidences for considerable sexual dimorphism in the cardiac aging process involving sex-biased aging genes and regulatory networks. Aging hearts are associated with a rewiring of RNA splicing programs, including sex- and age-dependent changes in exon usages and splice patterns that have the potential to influence cardiac protein structure and function. These changes represent an under-investigated aspect of cardiac aging that should be considered in the search for disease mechanisms.

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Metadata

Authors
Han, Y., Wennersten, S. A., Wright, J., Ludwig, R. W., Lau, E., & Lam, M. P. Y.
Affiliations
University of Colorado Anschutz (US)
Corresponding author
Lam, Maggie P. Y.
ORCID
Venue
American Journal of Physiology-Heart and Circulatory Physiology
Publisher
openRxiv
Published
2022-05-12
Volume
323
Issue
3
Pages
H538-H558
ISSN
0363-6135 (ISSN-L)
DOI
10.1101/2022.05.11.491401
PMC
PMC9448281
OpenAlex
W4289947631
Cited by
31
References
1
Citations by year
2026: 3 · 2025: 6 · 2024: 11 · 2023: 10 · 2022: 1
FWCI
2.35
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Colorado
  • National Institutes of Health (1r03od032666-01, R00-HL127302)
  • National Heart, Lung, and Blood Institute (F32HL149191, R00HL144829, R00HL127302, R21HL150456, R01HL141278)
  • NIH Office of the Director (R03OD032666)
  • University of Colorado School of Medicine, Anschutz Medical Campus
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords
cardiac aging, sex differences, exon usage, RNA-binding proteins, proteogenomics, mitochondrial metabolism, autophagy, translation (biology), cardiac remodeling
MeSH terms
Proteogenomics, Aging, Animals, Female, Male, RNA Splicing, RNA-Binding Proteins, Alternative Splicing, Mice

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