Biotinylation: a novel posttranslational modification linking cell autonomous circadian clocks with metabolism.

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), ACCß, 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.

Association Between the 10-Year ASCVD Risk Score and COVID-19 Complications Among Healthy Adults (Analysis from the National Cohort COVID Collaborative).

COVID-19 complications have been linked to worse outcomes among patients with established atherosclerotic cardiovascular disease (ASCVD). Less is known about the cumulative consequences of multiple ASCVD risk factors on COVID-19 outcomes. We evaluated the dose-response associations between 10-year ASCVD risk scores and COVID-19 complications. The National COVID-19 Cohort Collaborative collects electronic health record data from over 70 US health systems. Our analysis was limited to patients with positive COVID-19 tests without documented ASCVD events at the time of the first positive test. We evaluated the dose-response associations between 10-year ASCVD risk scores, categorized into categorized as low (<7.5%), intermediate (7.5% to 20.0%), or high (>20.0%), and COVID-19 complications, including hospitalizations and mortality. We reported the outcomes using multivariable-adjusted hazard ratios and 95% confidence intervals (CIs). Our cohort included 120,335 patients with documented positive COVID-19 test results who were free of ASCVD events. The mean age was 51.9 ± 16.1 years, 59.4% were women, 15.3% were Black, and 13.7% were Hispanic/Latino. Overall, 15,363 patients (12.8%) were hospitalized and 2,058 (1.7%) died. Patients at intermediate risk of developing ASCVD were had a 1.49 (95% CI 1.41 to 1.56) increased risk of hospitalization and 1.77 (95% CI 1.76 to 1.79) increased risk of mortality compared with patients at low risk. Patients at high risk had a 2.23 (95% CI 2.10 to 2.38) increased risk of hospitalization and a 5.98 (95% CI 5.93 to 6.03) increased risk of mortality. In conclusion, patients in this nationwide cohort at high risk of developing ASCVD are at substantially greater risk of COVID-19 complications. COVID-19 mitigation efforts should focus on these patient populations.