# METTL3 in Cardiac Benefits of Exercise in Diabetes

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $599,921

## Abstract

Summary / Abstract
 Diabetic cardiomyopathy is a major complication and the leading cause of death and disability in
patients with diabetes. Effective treatment to improve outcomes is lacking, and prognosis remains poor
for patients with diabetic cardiomyopathy. Thus, there is a growing unmet clinical need for novel
therapeutic approaches in diabetic cardiomyopathy. Exercise is an effective strategy for the prevention
and treatment of diabetic cardiomyopathy, however, the underlying molecular mechanisms remain poorly
understood. N6-methyladenosine (m6A) methylation is the most common form of RNA modification in
eukaryotes. METTL3, a m6A methyltransferase, has been implicated in cardiac development and cardiac
injury, however, little is known about the role of METTL3 in diabetic cardiomyopathy and cardiac benefit
of exercise in diabetes. Our preliminary studies found that (1) Cardiac METTL3 is downregulated in
diabetes and is upregulated by exercise. (2) Cardiomyocyte-specific knockout of METT3 cancels
beneficial effects of exercise on hearts from diabetes. (3) In vitro in primary cardiomyocytes,
overexpression of METTL3 protects cardiomyocytes from high glucose and palmitate-induced oxidative
stress and cell death. (4) METTL3 regulates YBX-1 in diabetic hearts. We hypothesize that METTL3 is
sufficient/necessary in cardiac benefits of exercise in diabetes and its does so through YBX-1. We will
test this hypothesis in three specific aims: (1) to determine the role of METTL3 in cardiac response to
exercise in diabetes, (2) to examine the effects of METTL3 in diabetic cardiomyopathy, and (3) to examine
the mechanisms by which METTL3 regulates diabetic cardiomyopathy. We anticipate that these studies
will shed new lights into the role of m6A (e.g., METTL3) in the pathophysiology of diabetic cardiomyopathy.
Moreover, these studies will establish clinically relevant approaches targeting METTL3 to combat
cardiomyopathy in patients with diabetes.
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## Key facts

- **NIH application ID:** 10776773
- **Project number:** 1R01HL171201-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Haobo Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $599,921
- **Award type:** 1
- **Project period:** 2024-07-05 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10776773

## Citation

> US National Institutes of Health, RePORTER application 10776773, METTL3 in Cardiac Benefits of Exercise in Diabetes (1R01HL171201-01). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10776773. Licensed CC0.

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