The circadian clock maintains cardiac function by regulating mitochondrial metabolism in mice.
Cardiac function is highly dependent on oxidative energy, which is produced by mitochondrial respiration. Defects in mitochondrial function are associated with both structural and functional abnormalities in the heart. Here, we show that heart-specific ablation of the circadian clock gene Bmal1 results in cardiac mitochondrial defects that include morphological changes and functional abnormalities, such as reduced enzymatic activities within the respiratory complex. Mice without cardiac Bmal1 function show a significant decrease in the expression of genes associated with the fatty acid oxidative pathway, the tricarboxylic acid cycle, and the mitochondrial respiratory chain in the heart and develop severe progressive heart failure with age. Importantly, similar changes in gene expression related to mitochondrial oxidative metabolism are also observed in C57BL/6J mice subjected to chronic reversal of the light-dark cycle; thus, they show disrupted circadian rhythmicity. These findings indicate that the circadian clock system plays an important role in regulating mitochondrial metabolism and thereby maintains cardiac function.
Department of Physiology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Akira
A
Kohsaka
Department of Physiology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Partha
P
Das
Department of Physiology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Izumi
I
Hashimoto
Department of Physiology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Tomomi
T
Nakao
Department of Physiology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Yoko
Y
Deguchi
Department of Physiology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Sabine S
SS
Gouraud
Department of Physiology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Hidefumi
H
Waki
First Department of Pathology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Yasuteru
Y
Muragaki
Department of Physiology, Wakayama Medical University School of Medicine, Wakayama, Japan.
Masanobu
M
Maeda
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D056930:ARNTL Transcription Factors / Q000378:metabolism; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism; D019748:Carbon-Carbon Double Bond Isomerases / Q000378:metabolism; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D002952:Citric Acid Cycle / Q000502:physiology; D004579:Electron Transport / Q000502:physiology; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D017440:Photoperiod; D019998:Racemases and Epimerases / Q000378:metabolism
D056930:ARNTL Transcription Factors; C038784:fatty acid oxidation complex; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D056926:CLOCK Proteins; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases