# Sex-specific regulation of myofibrillar function in the aging heart

> **NIH NIH K01** · UNIVERSITY OF COLORADO DENVER · 2020 · $116,805

## Abstract

PROJECT SUMMARY
Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure in patients over
65 years of age. Current therapeutic regimens do not effectively treat HFpEF; therefore, it is critical to
understand cellular mechanisms that cause this disease. Importantly, as women age, they have a higher risk of
developing HFpEF than men. It is not known what leads to this increased risk in females. Since a hallmark
feature of HFpEF is impaired relaxation, an important step in elucidating why women are at higher risk of
developing HFpEF is to understand how factors that are integral to relaxation differ between males and
females and how they change with age. This proposal seeks to elucidate how relaxation is regulated in males
and females in normal cardiac aging at the most basic level of cardiomyocyte function, the sarcomere. By
studying mechanical parameters of small bundles of sarcomeres, myofibrils, key differences in relaxation can
be defined and mechanisms that contribute to differences can be identified.
Preliminary studies demonstrate relaxation is prolonged in myofibrils isolated from hearts of female donors
over 60 years of age compared to myofibrils isolated from hearts of female donors between 20 and 40 years of
age. Additionally, there are also sex-differences in myofibril relaxation. Further preliminary studies also suggest
histone deacetylase 8 (HDAC8) may play a role in regulation of relaxation through acetylation of sarcomeric
proteins. This proposal will define sex differences in myofibril acetylation and relaxation in non-failing human
hearts from young adults (20-40 years of age) and older adults (> 60 years of age) (Aim 1). Since myofibril
relaxation changes observed in humans are recapitulated in adult (5 months of age) and older (20 months of
age) male and female mice, in vitro and in vivo mouse models will be used to interrogate changes in myofibril
relaxation in aging and with manipulation of HDAC8 (Aim 2).
Identifying how aging affects myofibril relaxation in males and females will provide valuable insight into
mechanisms that contribute to the development of HFpEF. This proposal is designed to expand Dr. Woulfe's
research to study cardiac aging. Dr. Woulfe's overall career goal is to study sex-differences in myofibril
mechanics across the lifespan and the training outlined in this proposal will allow her to develop key skills and
experience necessary to study cardiac aging. Dr. Woulfe has established a mentorship team with expertise in
aging, sex differences, and molecular biology of adenovirus generation and HDAC biology. Together, this team
of uniquely qualified mentors and Dr. Woulfe have developed a custom training plan tailored to provide the
skills and knowledge necessary to ensure appropriate research design and practices in a new area of
research.

## Key facts

- **NIH application ID:** 9952053
- **Project number:** 1K01AG066845-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** KATHLEEN WOULFE
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $116,805
- **Award type:** 1
- **Project period:** 2020-05-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952053

## Citation

> US National Institutes of Health, RePORTER application 9952053, Sex-specific regulation of myofibrillar function in the aging heart (1K01AG066845-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952053. Licensed CC0.

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