# Perinatal cardiomyocyte pruning driven by metabolic maturation: Opportunity for intervention

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $3,927

## Abstract

Project Summary of Parent R01
Cardiac myocyte number is a fundamental determinant of heart function which, due to progressive cell loss,
becomes especially important when the heart is stressed, such as when there is pediatric or adult heart
disease. Although intensive medical effort is focused on sparing myocytes during the disease process and
there is intense (as-yet unrealized) interest in restoring numbers through stem cell therapies, no work has been
done to address the large perinatal loss of cardiac myocytes. This is a therapeutic opportunity to increase life-
long cardiac myocyte number substantially. What is not known are the exact timing of the cell loss in the
peripartum period, and the signals in the near-birth cardiac milieu driving the cell loss.
In the same window during which myocyte loss occurs, the fetus faces increasing hypoxia, the fetal heart
undergoes metabolic maturation in preparation for the high-fat milk diet to come immediately after birth, and
thyroid hormone increases many-fold. The interaction of these three factors likely contribute to cardiac myocyte
loss via oxidative stress, autophagy and apoptosis. Further, male fetuses are notable for having “risky” in utero
growth strategies which may lead to increased sensitivity to pathological developmental programming. We
suspect that the interactions of these signaling pathways render hearts susceptible before birth, but that
oxidative stress and cell death can be suppressed by an antioxidant.
In this study we will use a large animal model (sheep) to examine both isolated (in culture) effects of these
regulators on metabolism and apoptosis, as well as their role in the more complex in utero environment. We
will use the Seahorse Bioanalyzer to measure cardiomyocyte respiration with different metabolic substrates
and under different test conditions. We will also measure cell death, as assessed by cell number, enzyme
release and activity, and apoptotic and autophagic pathway activation. We will tie these results in to reactive
oxygen species generation and activation of cell death pathways. We will also determine if melatonin
supplementation to reduce oxidative stress prevents the near-term loss of cardiac myocyte number.
Significance: Heart failure can be reduced by increasing the number of healthy cardiac myocytes. Myocyte
endowment is normally and substantially reduced around the time of birth in an event that represents a
powerful opportunity for intervention. We aim to increase myocyte number at birth by targeting the connection
between metabolic maturation, hypoxia and cell loss in a translational model applicable to human physiology.

## Key facts

- **NIH application ID:** 10476011
- **Project number:** 3R01HL142483-03S1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Sonnet Sky Jonker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,927
- **Award type:** 3
- **Project period:** 2022-01-04 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476011

## Citation

> US National Institutes of Health, RePORTER application 10476011, Perinatal cardiomyocyte pruning driven by metabolic maturation: Opportunity for intervention (3R01HL142483-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10476011. Licensed CC0.

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