# Discovery and characterization of lncRNAs involved in cardiac exercise phenotypes

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $399,600

## Abstract

Pathological hypertrophy is a common but not universal predecessor to heart failure (HF). The heart
also grows in response to exercise but this growth, termed physiological hypertrophy, does not generally lead
to adverse consequences and can even protect the heart against pathological stress. Moreover, recent work
from our group demonstrates that exercise substantially enhances endogenous cardiomyogenesis in the adult
heart. There is a fundamental gap in our understanding of how exercise mediates its benefits, including a
proliferative and potentially regenerative response in cardiomyocytes, and why cardiac hypertrophy can have
such different outcomes. Our over-arching hypothesis is that there are distinct forms of hypertrophy, which
appear superficially similar but employ fundamentally different mechanisms and thus have dramatically
different outcomes. Our long-term goal is to understand the pathways responsible for these differences and
learn whether they can be exploited therapeutically. The objective of the current application is to understand
the role of long noncoding RNAs (lncRNAs) in exercise-associated cardiac phenotypes.
 In preliminary studies, we identified 25 cardiac lncRNAs dynamically regulated by exercise, which we
term long noncoding Exercise Associated Transcripts or lncExACTs. Consistent with our over-arching
hypothesis, of the 25 lncExACTs identified, none change concordantly in exercise and pathological hypertrophy
or HF. Five lncExACTs are also altered in the disease models – but in opposite directions compared to exercise.
One of these, lncExACT1, is particularly intriguing because it decreases in exercised hearts and increases both
in animal HF models and human HF. Our preliminary data with lncExACT1 gain- and loss-of-function studies
in vitro and in vivo suggest it functions as a pivotal switch between physiological and pathological cardiac
hypertrophy and may regulate cardiomyocyte proliferation. lncExACT1 appears to work, at least in part,
through binding and inhibiting the microRNA, miR-222, which we have previously shown is necessary for
physiological cardiac growth and exercise-induced cardiomyogenesis.
 We propose to extend these studies in three integrated Specific Aims. In Aim 1, we will comprehensively
identify and functionally characterize in cardiomyocytes candidate lncRNAs differentially regulated in exercised
hearts in comparison to pressure-overload induced pathological hypertrophy and HF. In Aim 2, we will
characterize the biological roles of lncExACT1 in vivo in exercise and pressure-overload, as well as in a genetic
model of dilated cardiomyopathy. In Aim 3, we will delineate the mechanisms responsible for lncExACT1’s
cardiac effects, including binding to miRNAs and proteins as well as local genomic effects on gene expression.
 Successful completion of the proposed studies will advance our understanding of cardiac hypertrophy
and HF, as well as identifying novel pathways and potential therapeutic targets,...

## Key facts

- **NIH application ID:** 9885953
- **Project number:** 1R01HL146464-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ANTHONY ROSENZWEIG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,600
- **Award type:** 1
- **Project period:** 2019-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9885953

## Citation

> US National Institutes of Health, RePORTER application 9885953, Discovery and characterization of lncRNAs involved in cardiac exercise phenotypes (1R01HL146464-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9885953. Licensed CC0.

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