The circadian clock within the cardiomyocyte is essential for responsiveness of the heart to fatty acids

David J. Durgan, Nowice A. Trexler, Oluwaseun Egbejimi, Tracy A. McElfresh, Yun Suk Hee, Lauren E. Petterson, Chad A. Shaw, Paul E. Hardin, Molly S. Bray, Margaret P. Chandler, Chi Wing Chow, Martin E. Young

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

Cells/organs must respond both rapidly and appropriately to increased fatty acid availability; failure to do so is associated with the development of skeletal muscle and hepatic insulin resistance, pancreatic β-cell dysfunction, and myocardial contractile dysfunction. Here we tested the hypothesis that the intrinsic circadian clock within the cardiomyocytes of the heart allows rapid and appropriate adaptation of this organ to fatty acids by investigating the following: 1) whether circadian rhythms in fatty acid responsiveness persist in isolated adult rat cardiomyocytes, and 2) whether manipulation of the circadian clock within the heart, either through light/dark (L/D) cycle or genetic disruptions, impairs responsiveness of the heart to fasting in vivo. We report that both the intramyocellular circadian clock and diurnal variations in fatty acid responsiveness observed in the intact rat heart in vivo persist in adult rat cardiomyocytes. Reversal of the 12-h/12-h L/D cycle was associated with a re-entrainment of the circadian clock within the rat heart, which required5-8 days for completion. Fastingratsresultedintheinductionoffattyacid-responsivegenes, an effect that was dramatically attenuated 2 days after L/D cycle reversal. Similarly, a targeted disruption of the circadian clock within the heart, through overexpression of a dominant negative CLOCK mutant, severely attenuated induction of myocardial fatty acid-responsive genes during fasting. These studies expose a causal relationship between the circadian clock within the cardiomyocyte with responsiveness of the heart to fatty acids and myocardial triglyceride metabolism.

Original languageEnglish (US)
Pages (from-to)24254-24269
Number of pages16
JournalJournal of Biological Chemistry
Volume281
Issue number34
DOIs
StatePublished - Aug 25 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Durgan, D. J., Trexler, N. A., Egbejimi, O., McElfresh, T. A., Hee, Y. S., Petterson, L. E., Shaw, C. A., Hardin, P. E., Bray, M. S., Chandler, M. P., Chow, C. W., & Young, M. E. (2006). The circadian clock within the cardiomyocyte is essential for responsiveness of the heart to fatty acids. Journal of Biological Chemistry, 281(34), 24254-24269. https://doi.org/10.1074/jbc.M601704200