# Targeting Metabolism To Stimulate Adult Heart Regeneration

> **NIH NIH R56** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $392,783

## Abstract

Project Summary
Cardiovascular diseases are currently the major cause of morbidity and mortality in the world. This is due to the
inability of the adult mammalian heart to replace damaged tissue following injury. Identifying novel approaches
towards regenerating heart tissue following injury has significant therapeutic potential for heart failure patients.
Until recently, complete heart regeneration following injury has been observed only in lower vertebrates.
However, the ability of neonatal mice to regenerate their hearts following injury for a brief window after birth
indicates that uncovering the evolutionarily conserved mechanisms of cardiac regeneration has great potential
to treat human heart failure. The transition from embryonic/neonatal states to an adult state is accompanied with
a metabolic switch for energy utilization from glycolysis to oxidative phosphorylation. This metabolic switch leads
to a significant increase in reactive oxygen species (ROS) production from the mitochondria, which causes
cardiomyocyte DNA damage and results in cardiomyocyte cell cycle exit and loss of the endogenous cardiac
regeneration potential. What regulates this metabolic switch, and whether individual metabolites can regulate
ROS production and cardiac tissue regeneration remains unknown. Increased ROS production in ischemic
tissues has been demonstrated to occur as a result of the accumulation of the mitochondrial metabolite
succinate, and inhibition of succinate dehydrogenase (SDH) blocks succinate accumulation and is
cardioprotective against redox insult during ischemia/reperfusion (IR) injury. Thus, we hypothesized that changes
in oxygen levels following birth might trigger succinate accumulation and ROS production, which contributes to
cardiomyocyte cell-cycle exit in the postnatal heart. Our preliminary results demonstrate that injection of
succinate in the neonatal mouse heart results in inhibition of neonatal cardiomyocyte proliferation and
regeneration. Conversely, inhibition of SDH by malonate treatment after birth extends the window of
cardiomyocyte proliferation and regeneration in juvenile mice. Administration of Atpenin A5, a potent inhibitor of
SDH, induces a regenerative response in juvenile mice similar to malonate, demonstrating a central role for SDH
inhibition in promoting cardiomyocyte proliferation and regeneration following injury. Remarkably, malonate
treatment of adult mice following MI stimulates cardiomyocyte proliferation, revascularization, and results in
complete restoration of cardiac structure and function following infarction. More importantly, malonate treatment
at 1-week post-MI following the establishment of infarction and reduction of cardiac function results in myocardial
regeneration and restoration of cardiac function over time. Our overarching hypothesis is that malonate
metabolically reprograms the adult mammalian heart to a regenerative state via SDH inhibition. Our goal in this
proposal is to dissect the cellu...

## Key facts

- **NIH application ID:** 10296842
- **Project number:** 1R56HL155617-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Ahmed I Mahmoud
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $392,783
- **Award type:** 1
- **Project period:** 2021-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296842

## Citation

> US National Institutes of Health, RePORTER application 10296842, Targeting Metabolism To Stimulate Adult Heart Regeneration (1R56HL155617-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10296842. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*