# The methyltransferase Smyd1 regulates cardiac physiology

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $385,000

## Abstract

PROJECT SUMMARY
Coronary artery disease is the leading cause of death in the US and is the primary cause of chronic heart failure.
For patients with coronary artery disease, some advancements have been made clinically to restore blood flow
in diseased arteries and reduce myocardial injury from the resulting ischemia and subsequent reperfusion.
However, even with these advancements one quarter of patients will die or develop heart failure within 1 year.
Damage to the myocardium during ischemic injury includes deficiencies in metabolism and energetics. Some
key epigenetic regulators can prevent or reduce ischemic injury and pathological remodeling in murine models,
however, their ubiquitous expression has made them unsuitable for therapeutic targeting in humans, thus far. In
contrast, we recently identified the only known myocyte-specific epigenetic regulator of mitochondrial energetics
and metabolism – the histone lysine methyltransferase Smyd1 – which holds great therapeutic potential given
its tissue-specific expression. Specifically, we performed the first analysis of Smyd1 function in the adult
myocardium using inducible, cardiomyocyte-specific Smyd1 knockout mice and showed that loss of Smyd1 leads
to dysregulated cardiac metabolism and suppressed mitochondrial respiration, ultimately leading to heart failure
(published in AJP). Subsequently we showed that down-regulation of mitochondrial energetics is an early event
in these knockout mice (occurring before the onset of cardiac dysfunction) and results, at least in part, from
Smyd1’s regulation of PGC-1α transcription (published in PNAS). To further understand Smyd1’s role in
regulating cardiac physiology we recently generated transgenic mice allowing inducible, cardiomyocyte-specific
overexpression of the Smyd1a isoform (the mouse ortholog to human SMYD1) and subjected these mice to
permanent occlusion of the LAD. Our unpublished preliminary results show that Smyd1a gain-of-function can
enhance mitochondrial respiration and protect from ischemic injury, although how this is accomplished
molecularly is unknown. In addition, our preliminary data from these mice show increased mitochondrial cristae
formation and stabilization of respiratory chain supercomplexes within the cristae, concomitant with increased
Opa1 expression, a known driver of cristae morphology. These results implicate Opa1 as a novel, functionally
important downstream target of Smyd1a whereby cardiomyocytes upregulate energy efficiency, protecting them
from ischemic injury. Our overarching hypothesis is that Smyd1a protects from ischemic injury by regulating
mitochondrial energetics and enhancing respiration efficiency in the cardiomyocyte through regulation of both:
1) PGC-1α expression (a regulator of electron transport chain gene expression) and 2) OPA1-mediated cristae
remodeling and stabilization of electron transport chain supercomplexes. We will test this hypothesis in our
transgenic mice which conditionally overexpress ...

## Key facts

- **NIH application ID:** 10880694
- **Project number:** 5R01HL161045-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Sarah Franklin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2022-07-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880694

## Citation

> US National Institutes of Health, RePORTER application 10880694, The methyltransferase Smyd1 regulates cardiac physiology (5R01HL161045-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10880694. Licensed CC0.

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