Circadian regulation of cardiac metabolism
Lilei Zhang, Mukesh K. Jain
Lilei Zhang, Mukesh K. Jain
Published August 2, 2021
Citation Information: J Clin Invest. 2021;131(15):e148276. https://doi.org/10.1172/JCI148276.
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Circadian regulation of cardiac metabolism

Abstract

Circadian rhythm evolved to allow organisms to coordinate intrinsic physiological functions in anticipation of recurring environmental changes. The importance of this coordination is exemplified by the tight temporal control of cardiac metabolism. Levels of metabolites, metabolic flux, and response to nutrients all oscillate in a time-of-day–dependent fashion. While these rhythms are affected by oscillatory behavior (feeding/fasting, wake/sleep) and neurohormonal changes, recent data have unequivocally demonstrated an intrinsic circadian regulation at the tissue and cellular level. The circadian clock — through a network of a core clock, slave clock, and effectors — exerts intricate temporal control of cardiac metabolism, which is also integrated with environmental cues. The combined anticipation and adaptability that the circadian clock enables provide maximum advantage to cardiac function. Disruption of the circadian rhythm, or dyssynchrony, leads to cardiometabolic disorders seen not only in shift workers but in most individuals in modern society. In this Review, we describe current findings on rhythmic cardiac metabolism and discuss the intricate regulation of circadian rhythm and the consequences of rhythm disruption. An in-depth understanding of the circadian biology in cardiac metabolism is critical in translating preclinical findings from nocturnal-animal models as well as in developing novel chronotherapeutic strategies.

Authors

Lilei Zhang, Mukesh K. Jain

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Figure 3

Integrated circadian cardiac metabolic regulation.

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Integrated circadian cardiac metabolic regulation. The slave clock KLF15...
The slave clock KLF15 integrates signals from both the core clock (BMAL1) and external metabolic clues (diet, exercise, heart disease, and aging). In turn, KLF15 regulates downstream oscillatory target genes in the heart, both by activating them (e.g., Nampt) and by repressing their oscillation (e.g., Nr4a1). Critical pathways (e.g., NAD+) may be dually regulated by both the core clock and the slave clock to enable tight temporal control, as well as flexibility between anticipation and adaptation. Circadian regulation of NAD+ allows coordinated catabolism and ROS clearance, which is essential for myocardium homeostasis. REV, REV-ERB.