# Circadian Regulation of mTOR Signaling in the Failing Heart

> **NIH NIH F32** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $64,554

## Abstract

Project Summary
Cardiovascular disease (CVD) is the leading cause of death in the United States with 25% of
Americans suffering from one or more forms of CVD. Although procedural interventions have
markedly increased survival following acute adverse cardiac events, heart failure (HF) incidence
has more than doubled over the past 30 years. A plethora of putative mechanisms have been
proposed in the pathogenesis of heart failure, ranging from extra-cardiac (e.g. volume and
pressure overload, atherosclerosis, and inflammation) to intra-cardiac (e.g. extracellular matrix,
signaling, enhanced protein synthesis, and metabolism). Despite this wealth of knowledge,
significant barriers still exist in understanding the etiology of HF and translating this information
to patient care.
Hypertrophic growth is considered a foundational event in adverse cardiac remodeling in HF
patients. Prior studies indicate that both sensitivity of the heart to pro-hypertrophic stimuli, and
the processes critical for hypertrophic growth (e.g., protein synthesis) are exacerbated at the
beginning of the sleep period, and that this time-of-day-dependence is mediated by a molecular
timekeeping mechanism in cardiomyocytes. Namely the cardiomyocyte circadian clock (CCC).
Interestingly, cardiomyocyte-specific BMAL1 knockout (CBK; BMAL1 is a critical clock
component) temporally suspends the CCC at the beginning of the sleep phase, such that cardiac
protein synthesis is chronically high throughout the day, leading to cardiomyocyte hypertrophy,
adverse cardiac remodeling, and ultimately dilated cardiomyopathy. A key regulator of protein
synthesis is mammalian target of rapamycin (mTOR), and we have recently reported that mTOR
is chronically activated in CBK hearts, through an as yet undefined mechanism. Recent unbiased
small RNA sequencing of wild-type (WT) and CBK hearts has revealed that miR-582 exhibits a
2-fold oscillation in WT hearts which is abrogated by the loss of BMAL1; miR-582 is chronically
elevated in CBK hearts. A predicted target of miR-582 is Deptor (DEPDC6), a negative regulator
of mTOR activity. Interestingly, we find that Deptor has a 2-fold oscillation in WT hearts, with
lowest levels at the beginning of the sleep phase,and is chronically low in CBK hearts. Collectively,
these observations have led to the hypothesis that the CCC facilitates cardiac growth/repair
during the sleep period through the miR-582/Deptor/mTOR axis, and that disruption of the CCC
chronically perturbs this signaling axis, resulting in cardiomyocyte hypertrophy and adverse
cardiac remodeling.

## Key facts

- **NIH application ID:** 10065958
- **Project number:** 1F32HL154531-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Mary neslund Latimer
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,554
- **Award type:** 1
- **Project period:** 2020-09-21 → 2021-09-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065958

## Citation

> US National Institutes of Health, RePORTER application 10065958, Circadian Regulation of mTOR Signaling in the Failing Heart (1F32HL154531-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065958. Licensed CC0.

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