# Metabolic Reprogramming of the Adult heart to a Regenerative State

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $410,290

## Abstract

Project Summary
Heart failure with reduced ejection fraction is a major public health burden with high morbidity and mortality.
Identifying novel approaches towards regenerating heart tissue has significant therapeutic potential for heart
failure patients. Similar to lower vertebrates, neonatal mice can regenerate their hearts following injury for a brief
window after birth. Remarkably, we recently discovered that inhibition of the mitochondrial enzyme succinate
dehydrogenase (SDH) can promote adult cardiac regeneration following myocardial infarction (MI). Our results
are distinct from the previous studies demonstrating a cardioprotective role for SDH inhibition against the redox
insult during ischemia/reperfusion injury, as we demonstrate that SDH inhibition does not protect the heart
against MI-induced infarction. The metabolic switch from glycolysis to fatty acid oxidation in the postnatal heart
contributes to cardiomyocyte cell cycle exit and loss of endogenous cardiac regeneration potential. SDH, also
known as mitochondrial complex II, plays a central role in regulating cellular metabolism as it is involved in both
the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). Our recently published study
demonstrates that inhibition of SDH by malonate treatment of adult mice following myocardial infarction
stimulates cardiomyocyte proliferation, revascularization, and results in restoration of cardiac structure and
function following infarction. Remarkably, our metabolite analysis following SDH inhibition demonstrates dynamic
metabolic changes in the uninjured adult heart. Our overarching hypothesis is that SDH inhibition metabolically
reprograms the adult heart to a regenerative state. To define the role of SDH in adult heart regeneration, we will
pursue the following aims: 1) Elucidate the metabolic and cellular mechanisms underlying post-MI regeneration
following SDH inhibition; 2) Define the molecular mechanisms by which SDH inhibition promotes post-MI
regeneration; 3) Determine the role of SDH inhibition by malonate on regenerative potential following myocardial
infarction in a porcine model. Our proposed experiments will define the mechanisms by which SDH inhibition
promotes cardiac regeneration, as well as establish the therapeutic potential of SDH inhibition in large animal
hearts which exhibit distinct physiology from the mouse heart. Collectively, our results reveal a novel role for
SDH inhibition in promoting heart regeneration following myocardial infarction, and this proposal will generate
important results that will lead to novel therapeutic strategies to regenerate the adult heart following infarction.

## Key facts

- **NIH application ID:** 10805370
- **Project number:** 5R01HL166256-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Ahmed I Mahmoud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,290
- **Award type:** 5
- **Project period:** 2023-03-15 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805370

## Citation

> US National Institutes of Health, RePORTER application 10805370, Metabolic Reprogramming of the Adult heart to a Regenerative State (5R01HL166256-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10805370. Licensed CC0.

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