The Role of Two Homologous E3 Ligases in Muscle Physiology

Ubiquitin-mediated proteasomal degradation is an essential cellular function that is coordinated by three key components: E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligases. There are an estimated 600 E3 ligases, some of which share high sequence homology; however, the functional significance often remains unknown. FBXL3 and FBXL21 are two homologous E3 ligases that have previously been reported to dictate circadian periodicity, with FBXL3 being the dominant E3 ligase and FBXL21 playing a regulatory role. A recent Yeast Two-Hybrid screen revealed a new shared target of FBXL3 and FBXL21: Telethonin (also known as TCAP). TCAP is a sarcomeric z-disc protein expressed in cardiac and skeletal muscle that is critical to proper structure and function of muscles. Through preliminary experiments, we identified TCAP as a novel shared target substrate of FBXL3 and FBXL21. Here we report that FBXL3 and FBXL21 both accelerate TCAP degradation; however, FBXL21 is the more potent E3 ligase. This novel finding underlines the importance of substrate specificity and serves as a paradigm for future mechanistic studies of E3 ligase homologous pairs. Additionally, the findings reported here will facilitate further studies investigating the role of FBXL3/21 in muscle physiology

Nightshift Work and Nighttime Eating Are Associated With Higher Insulin and Leptin Levels in Hospital Nurses

BackgroundCircadian misalignment between behaviors such as feeding and endogenous circadian rhythms, particularly in the context of shiftwork, is associated with poorer cardiometabolic health. We examined whether insulin and leptin levels differ between dayshift versus nightshift nurses, as well as explored whether the timing of food intake modulates these effects in nightshift workers.MethodsFemale nurses (N=18; 8 dayshift and 10 nightshift) completed daily diet records for 8 consecutive days. The nurses then completed a 24-h inpatient stay, during which blood specimens were collected every 3 h (beginning at 09:00) and meals were consumed at regular 3-h intervals (09:00, 12:00, 15:00, and 18:00). Specimens were analyzed for insulin and leptin levels, and generalized additive models were used to examine differences in mean insulin and leptin levels.ResultsMean insulin and leptin levels were higher in nightshift nurses by 11.6 ± 3.8 mU/L (p=0.003) and 7.4 ± 3.4 ng/ml (p=0.03), respectively, compared to dayshift nurses. In an exploratory subgroup analysis of nightshift nurses, predominately eating at night (21:00 – 06:00) was associated with significantly higher insulin and leptin levels than consuming most calories during the daytime (06:00 – 21:00).ConclusionsIn our study of hospital nurses, working the nightshift was associated with higher insulin and leptin levels, and these effects were driven by eating predominately at night. We conclude that although nightshift work may raise insulin and leptin levels, eating during the daytime may attenuate some of the negative effects of nightshift work on metabolic health