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Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids

OBJECTIVE: Mitochondrial capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian cycle of energy metabolism, but little is known about how circadian timing of exogenous glucocorticoid dosing directly regu...

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Autores principales: Wintzinger, Michelle, Panta, Manoj, Miz, Karen, Prabakaran, Ashok D., Durumutla, Hima Bindu, Sargent, Michelle, Peek, Clara Bien, Bass, Joseph, Molkentin, Jeffery D., Quattrocelli, Mattia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243158/
https://www.ncbi.nlm.nih.gov/pubmed/35717025
http://dx.doi.org/10.1016/j.molmet.2022.101528
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author Wintzinger, Michelle
Panta, Manoj
Miz, Karen
Prabakaran, Ashok D.
Durumutla, Hima Bindu
Sargent, Michelle
Peek, Clara Bien
Bass, Joseph
Molkentin, Jeffery D.
Quattrocelli, Mattia
author_facet Wintzinger, Michelle
Panta, Manoj
Miz, Karen
Prabakaran, Ashok D.
Durumutla, Hima Bindu
Sargent, Michelle
Peek, Clara Bien
Bass, Joseph
Molkentin, Jeffery D.
Quattrocelli, Mattia
author_sort Wintzinger, Michelle
collection PubMed
description OBJECTIVE: Mitochondrial capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian cycle of energy metabolism, but little is known about how circadian timing of exogenous glucocorticoid dosing directly regulates heart metabolism through cardiomyocyte-autonomous mechanisms. While chronic once-daily intake of glucocorticoids promotes metabolic stress and heart failure, we recently discovered that intermittent once-weekly dosing of exogenous glucocorticoids promoted muscle metabolism in normal and obese skeletal muscle. However, the effects of glucocorticoid intermittence on heart metabolism and heart failure remain unknown. Here we investigated the extent to which circadian time of dosing regulates the effects of the glucocorticoid prednisone in heart metabolism and function in conditions of single pulse or chronic intermittent dosing. METHODS AND RESULTS: In WT mice, we found that prednisone improved cardiac content of NAD(+) and ATP with light-phase dosing (ZT0), while the effects were blocked by dark-phase dosing (ZT12). The drug effects on mitochondrial function were cardiomyocyte-autonomous, as shown by inducible cardiomyocyte-restricted glucocorticoid receptor (GR) ablation, and depended on an intact cardiomyocyte clock, as shown by inducible cardiomyocyte-restricted ablation of Brain and Muscle ARNT-like 1 (BMAL1). Conjugating time-of-dosing with chronic intermittence, we found that once-weekly prednisone improved metabolism and function in heart after myocardial injury dependent on circadian time of intake, i.e. with light-phase but not dark-phase dosing. CONCLUSIONS: Our study identifies cardiac-autonomous mechanisms through which circadian-specific intermittent dosing reconverts glucocorticoid drugs to metabolic boosters for the heart.
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spelling pubmed-92431582022-07-01 Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids Wintzinger, Michelle Panta, Manoj Miz, Karen Prabakaran, Ashok D. Durumutla, Hima Bindu Sargent, Michelle Peek, Clara Bien Bass, Joseph Molkentin, Jeffery D. Quattrocelli, Mattia Mol Metab Original Article OBJECTIVE: Mitochondrial capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian cycle of energy metabolism, but little is known about how circadian timing of exogenous glucocorticoid dosing directly regulates heart metabolism through cardiomyocyte-autonomous mechanisms. While chronic once-daily intake of glucocorticoids promotes metabolic stress and heart failure, we recently discovered that intermittent once-weekly dosing of exogenous glucocorticoids promoted muscle metabolism in normal and obese skeletal muscle. However, the effects of glucocorticoid intermittence on heart metabolism and heart failure remain unknown. Here we investigated the extent to which circadian time of dosing regulates the effects of the glucocorticoid prednisone in heart metabolism and function in conditions of single pulse or chronic intermittent dosing. METHODS AND RESULTS: In WT mice, we found that prednisone improved cardiac content of NAD(+) and ATP with light-phase dosing (ZT0), while the effects were blocked by dark-phase dosing (ZT12). The drug effects on mitochondrial function were cardiomyocyte-autonomous, as shown by inducible cardiomyocyte-restricted glucocorticoid receptor (GR) ablation, and depended on an intact cardiomyocyte clock, as shown by inducible cardiomyocyte-restricted ablation of Brain and Muscle ARNT-like 1 (BMAL1). Conjugating time-of-dosing with chronic intermittence, we found that once-weekly prednisone improved metabolism and function in heart after myocardial injury dependent on circadian time of intake, i.e. with light-phase but not dark-phase dosing. CONCLUSIONS: Our study identifies cardiac-autonomous mechanisms through which circadian-specific intermittent dosing reconverts glucocorticoid drugs to metabolic boosters for the heart. Elsevier 2022-06-16 /pmc/articles/PMC9243158/ /pubmed/35717025 http://dx.doi.org/10.1016/j.molmet.2022.101528 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Wintzinger, Michelle
Panta, Manoj
Miz, Karen
Prabakaran, Ashok D.
Durumutla, Hima Bindu
Sargent, Michelle
Peek, Clara Bien
Bass, Joseph
Molkentin, Jeffery D.
Quattrocelli, Mattia
Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids
title Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids
title_full Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids
title_fullStr Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids
title_full_unstemmed Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids
title_short Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids
title_sort impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243158/
https://www.ncbi.nlm.nih.gov/pubmed/35717025
http://dx.doi.org/10.1016/j.molmet.2022.101528
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