title: Biotinylation: a novel posttranslational modification linking cell autonomous circadian clocks with metabolism.
abstract: Circadian clocks are critical modulators of metabolism. However, mechanistic links between cell autonomous clocks and metabolic processes remain largely unknown. Here, we report that expression of the biotin transporter slc5a6 gene is decreased in hearts of two distinct genetic mouse models of cardiomyocyte-specific circadian clock disruption [i.e., cardiomyocyte-specific CLOCK mutant (CCM) and cardiomyocyte-specific BMAL1 knockout (CBK) mice]. Biotinylation is an obligate posttranslational modification for five mammalian carboxylases: acetyl-CoA carboxylase α (ACCα), ACCβ, pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). We therefore hypothesized that the cardiomyocyte circadian clock impacts metabolism through biotinylation. Consistent with decreased slc5a6 expression, biotinylation of all carboxylases is significantly decreased (10-46%) in CCM and CBK hearts. In association with decreased biotinylated ACC, oleate oxidation rates are increased in both CCM and CBK hearts. Consistent with decreased biotinylated MCC, leucine oxidation rates are significantly decreased in both CCM and CBK hearts, whereas rates of protein synthesis are increased. Importantly, feeding CBK mice with a biotin-enriched diet for 6 wk normalized myocardial 1) ACC biotinylation and oleate oxidation rates; 2) PCC/MCC biotinylation (and partially restored leucine oxidation rates); and 3) net protein synthesis rates. Furthermore, data suggest that the RRAGD/mTOR/4E-BP1 signaling axis is chronically activated in CBK and CCM hearts. Finally we report that the hepatocyte circadian clock also regulates both slc5a6 expression and protein biotinylation in the liver. Collectively, these findings suggest that biotinylation is a novel mechanism by which cell autonomous circadian clocks influence metabolic pathways.
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Lan
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: J Austin
authors.initials: JA
authors.lastname: Hamm
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Alex
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: David
authors.initials: D
authors.lastname: Sams
authors.affiliation: Department of Biological Sciences, Federal University of Sao Paulo, Diadema, Sao Paulo, Brazil;
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Peliciari-Garcia
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Graham R
authors.initials: GR
authors.lastname: McGinnis
authors.affiliation: Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Bailey
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Glenn C
authors.identifier: 0000-0002-8195-9605
authors.initials: GC
authors.lastname: Rowe
authors.affiliation: Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: John C
authors.identifier: 0000-0001-7180-9948
authors.initials: JC
authors.lastname: Chatham
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; meyoung@uab.edu.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D001710:Biotin / Q000008:administration & dosage / Q000378:metabolism; D019921:Biotinylation; D056926:CLOCK Proteins / Q000235:genetics; D019735:Carbon-Carbon Ligases / Q000378:metabolism; D019755:Carbon-Carbon Lyases / Q000378:metabolism*; D021081:Chronobiology Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D057906:Circadian Clocks / Q000235:genetics; D004195:Disease Models, Animal; D004734:Energy Metabolism; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D008297:Male; D043586:Methylmalonyl-CoA Decarboxylase / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D011766:Pyruvate Carboxylase / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D013997:Time Factors
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D027981:Symporters; C119981:biotin transporter; D001710:Biotin; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D019755:Carbon-Carbon Lyases; D019735:Carbon-Carbon Ligases; D011766:Pyruvate Carboxylase; C000616953:ACC1 protein, mouse; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase; C021573:methylcrotonoyl-CoA carboxylase; D043586:Methylmalonyl-CoA Decarboxylase
keywords: biotin; chronobiology; heart; liver; metabolism; nutrition