Restless legs syndrome, periodic limb movements of sleep, and subclinical cardiovascular disease.

Restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) have been variably implicated in risk for cardiovascular disease (CVD), but there is lack of consensus on these relationships. We sought to assess subclinical CVD measures and RLS/PLMS in a large cohort to further evaluate these associations. The Emory Center for Health Discovery and Well Being cohort is composed of employed adults, with subclinical CVD measures including endothelial function (flow-mediated vasodilation), microvascular function (reactive hyperemia index, RHI), arterial stiffness (pulse wave velocity and augmentation index), and carotid intima-media thickness (cIMT). Participants were grouped based on presence (N = 50) or absence (N = 376) of RLS and subclinical CVD measures compared between groups. A subset of participants (n = 40) underwent ambulatory monitoring for PLMS and obstructive sleep apnea. PLMS association with subclinical CVD measures was assessed. RLS status was significantly associated with flow-mediated dilation in univariate analyses but not after controlling for potential confounders; RLS was not associated with other subclinical CVD measures. PLMS were significantly correlated with the RHI, augmentation index, and cIMT in univariate analyses; only the association between PLMS and cIMT remained significant (p = 0.04) after controlling for RLS status, age, apnea-hypopnea index, hyperlipidemia, and hypertension. The observed association between higher PLMS and greater cIMT suggests that PLMS may be a marker of subclinical CVD. Further work is needed to determine the relationship between PLMS and CVD risk. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-023-00497-7.

Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy.

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes, whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here, we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization. This results in elevated levels of BMAL1 and a dysfunctional clock that displays abnormal timekeeping under constant conditions and exaggerated responses to phase resetting. Genetically lowering the dose of BMAL1 rescues circadian behavioral phenotypes in TSC mouse models. These findings indicate that BMAL1 deregulation is a feature of the mTOR-activated state and suggest a molecular mechanism for mitigating circadian phenotypes in a neurodevelopmental disorder.