# Relationship between circadian disruption, cardiac GH/IGF-1 signaling, and heart failure

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2020 · —

## Abstract

Cardiovascular disease (CVD) is a major cause of mortality in the U.S. Among CVDs, heart failure (HF) is a sig-
nificant public health burden contributing not only to human suffering, but also to increasing healthcare expend-
itures. CVDs arise in the setting of complex gene-environment interactions; the underlying genetics within an in-
dividual influences how environmental and hormonal stimuli and stresses affect cardiac function and cause path-
ology. The cardiomyocyte circadian clock is a genetically-programmed intrinsic cell-autonomous molecular
mechanism that allows the heart to anticipate environmental stimuli and stresses and subsequently facilitates
responses essential for maintaining cardiac function. Disruption of the circadian clock mechanism in mice and
humans (e.g., through genetic polymorphisms or environmental alterations such as shift work, sleep disturbance,
or eating behavior modulation) negatively impact cardiometabolic health. Furthermore, germline deletion of
BMAL1, a core transcription factor component of the clock mechanism, yields an age onset dilated cardiomyo-
pathy and reduced lifespan. We recently found that BMAL1 deletion specifically from cardiomyocytes
(CBK mouse) recapitulates this pathologic phenotype, exposing an essential role for the clock in the
heart. However, the mechanism by which cardiomyocyte circadian clock disruption leads to cardiomyopathy is
unknown. Multiple endocrine system components are circadian. Evidence is emerging that cell autonomous cir-
cadian clocks not only drive the temporal secretion of hormones, but also modulate time-of-day-dependent target
tissue sensitivity to these hormones. In doing so, circadian clocks add a new layer to homeostasis; not only do
the level of, and the sensitivity to, a stimulus play an important role, but also the timing. Circulating levels of the
pituitary hormone, growth hormone (GH), exhibit notable circadian rhythm in humans. In contrast, nothing is
known about rhythms in GH sensitivity. Chronic GH elevation yields cardiomegaly and HF. GH exerts many of
its biological actions by inducing insulin-like growth factor-1 (IGF-1); a mouse model of cardiomyocyte-specific
IGF-1 overexpression results in hypertrophic cardiomyopathy. Our recent preliminary data suggest time-of-day-
dependent oscillation of GH sensitivity in the heart, which depends on the cardiomyocyte circadian clock. More-
over, CBK hearts exhibit greater GH sensitivity, with elevated cardiac IGF-1 gene expression, cardiomyocyte
hypertrophy, and HF. Together, these observations lead us to hypothesize that the cardiomyocyte circa-
dian clock modulates GH sensitivity, and that disruption of this mechanism confers local IGF-1-mediated
cardiac hypertrophy and HF via augmented GH sensitivity. Accordingly, we will test the hypotheses that:
Aim 1. Cardiomyocyte circadian clock modulation of GH sensitivity is essential for maintenance of
cardiac function. We will determine whether: 1A. The cardiomyocyte circ...

## Key facts

- **NIH application ID:** 9898294
- **Project number:** 5I01BX003718-04
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Stuart J Frank
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898294

## Citation

> US National Institutes of Health, RePORTER application 9898294, Relationship between circadian disruption, cardiac GH/IGF-1 signaling, and heart failure (5I01BX003718-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898294. Licensed CC0.

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