Cardiac response to adrenergic stress differs by sex and across the lifespan

GeroScience (2021)Cite this article

Abstract

The aging heart is well-characterized by a diminished responsiveness to adrenergic activation. However, the precise mechanisms by which age and sex impact adrenergic-mediated cardiac function remain poorly described. In the current investigation, we compared the cardiac response to adrenergic stress to gain mechanistic understanding of how the response to an adrenergic challenge differs by sex and age. Juvenile (4 weeks), adult (4–6 months), and aged (18–20 months) male and female mice were treated with the β-agonist isoproterenol (ISO) for 1 week. ISO-induced morphometric changes were age- and sex-dependent as juvenile and adult mice of both sexes had higher left ventricle weights while aged mice did not increase cardiac mass. Adults increased myocyte cell size and deposited fibrotic matrix in response to ISO, while juvenile and aged animals did not show evidence of hypertrophy or fibrosis. Juvenile females and adults underwent expected changes in systolic function with higher heart rate, ejection fraction, and fractional shortening. However, cardiac function in aged animals was not altered in response to ISO. Transcriptomic analysis identified significant differences in gene expression by age and sex, with few overlapping genes and pathways between groups. Fibrotic and adrenergic signaling pathways were upregulated in adult hearts. Juvenile hearts upregulated genes in the adrenergic pathway with few changes in fibrosis, while aged mice robustly upregulated fibrotic gene expression without changes in adrenergic genes. We suggest that the response to adrenergic stress significantly differs across the lifespan and by sex. Mechanistic definition of these age-related pathways by sex is critical for future research aimed at treating age-related cardiac adrenergic desensitization.

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Acknowledgements

The authors thank Jacob Schlatter and Sydney Polson for technical assistance and the Wyoming INBRE Bioinformatics Core for assistance with data analysis.

Funding

This project was supported by NIH/NIA 1K01 AG058810-01A1 (DRB), NIH/NICHD 2K12 HD057022-11 (KCW), University of Wyoming College of Health Sciences Faculty in Aid (DRB), University of Colorado Lorna Grindlay Moore Faculty Launch Award (KCW), and Institutional Development Award 2-P20-GM-103432.

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Author notes

  1. Kathleen C. Woulfe and Danielle R. Bruns contributed equally to this work.

Affiliations

  1. Division of Kinesiology and Health, University of Wyoming, Laramie, WY, USA

    Aykhan Yusifov, Ross F. Cook, Benjamin D. McNair, Emily E. Schmitt & Danielle R. Bruns

  2. Wyoming INBRE Data Science Core, Laramie, WY, USA

    Vikram E. Chhatre

  3. School of Medicine, WWAMI Medical Education, University of Washington, Seattle, WA, USA

    Jacob M. Zumo, Emily E. Schmitt & Danielle R. Bruns

  4. Divisions of Cardiology and Geriatric Medicine, University of Colorado-Denver, Aurora, CO, USA

    Kathleen C. Woulfe

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  1. Aykhan Yusifov
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Yusifov, A., Chhatre, V.E., Zumo, J.M. et al. Cardiac response to adrenergic stress differs by sex and across the lifespan. GeroScience (2021). https://doi.org/10.1007/s11357-021-00345-x

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Keywords

  • Cardiac
  • Sex Differences
  • Adrenergic
  • Juvenile
  • RNA sequencing
  • Lifespan