# CHRONO-MECHANISMS of CARDIOMETABOLIC PHARMACOLOGY

> **NIH NIH R56** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $397,500

## Abstract

PROJECT SUMMARY
Glucocorticoid steroids are conserved pleiotropic hormones regulating the circadian cycle of energy utilization
and storage in virtually all our organs. Nutrient metabolism in the heart is critical to adapt the high energy
demand to circadian oscillations and/or diseased states like diabetic cardiomyopathy. Glucocorticoids exert
their effects through the glucocorticoid receptor (GR), which is required for normal heart function. Indeed,
synthetic glucocorticoids are routinely used to rescue cardiac conditions of metabolic acidosis and depressed
function, such as low cardiac output syndrome. However, chronic GR over-stimulation with synthetic
glucocorticoids promotes metabolic syndrome and cardiovascular diseases. Thus, the molecular and circadian
effects of synthetic glucocorticoids and their receptor on cardiac metabolism are still unresolved. Using
dystrophic mice as model of chronic striated muscle injury, I discovered that intermittent dosing (once-weekly)
of glucocorticoids boosts nutrient utilization and insulin sensitivity in dystrophic muscle and heart. Here I
postulate that intermittent glucocorticoids improve cardiometabolic health beyond the dystrophic heart and can
be exploited to combat diabetic cardiomyopathy. In mice, oscillations of endogenous corticosterone and
circadian clock factors create a critical time window for acute GR responsiveness to pharmacological activation
in the early diurnal phase. Indeed, I found that diurnal – but not nocturnal – regimens of intermittent prednisone
improved cardiac function and metabolism in wildtype hearts. Diurnal administration was critical for the
prednisone-driven GR program to boost mitochondrial capacity and activate the metabolic regulators KLF15
and AMPK. Also, diurnal prednisone reduced 3-hydroxyisobutyrate (3-HIB), biomarker of impaired catabolism
of branched chain amino acids (BCAA) and insulin resistance in diabetes. Thus, I hypothesize that chrono-
pharmacology with diurnal glucocorticoids promotes cardiometabolic health through GR, KLF15 and AMPK
activation, and reduces 3-HIB as biomarker of metabolic rescue in diabetic cardiomyopathy. To test this
hypothesis, we will articulate the project to test three complementary mechanisms: in Aim 1, we will test the
requirement for GR and the clock factor BMAL in the effects of diurnal prednisone on mitochondrial capacity in
heart; in Aim 2, we will define requirement and epigenomic mechanisms for the GR-activated KLF15 in
reshaping nutrient utilization in cardiomyocytes in response to prednisone chrono-dosing; in Aim 3, we will
determine the role of AMPK and BCAA oxidation in mediating the effects of diurnal intermittent prednisone on
metabolic flexibility and 3-HIB levels in diabetic cardiomyopathy. This proposal charts a novel path to
cardiometabolic rescue by exploiting the circadian-gated response to synthetic glucocorticoids in heart.
Defining unprecedented mechanisms of interplay between glucocorticoid cascades and ci...

## Key facts

- **NIH application ID:** 10271560
- **Project number:** 1R56HL158531-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Mattia Quattrocelli
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,500
- **Award type:** 1
- **Project period:** 2021-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271560

## Citation

> US National Institutes of Health, RePORTER application 10271560, CHRONO-MECHANISMS of CARDIOMETABOLIC PHARMACOLOGY (1R56HL158531-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10271560. Licensed CC0.

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