Sleep and physical activity - the dynamics of bi-directional influences over a fortnight.

STUDY OBJECTIVES: The day-to-next day predictions between physical activity (PA) and sleep are not well known, although they are crucial for advancing public health by delivering valid sleep and physical activity recommendations. We used Big Data to examine cross-lagged time-series of sleep and PA over 14 days and nights. METHODS: Bi-directional cross-lagged autoregressive pathways over 153,154 days and nights from 12,638 Polar watch users aged 18-60 years (M = 40.1 SD = 10.1; 44.5% female) were analyzed with cross-lagged panel data modeling (RI-CPL). We tested the effects of moderate-to-vigorous physical activity (MVPA) vs. high intensity PA (vigorous, VPA) on sleep duration and quality, and vice versa. RESULTS: Within-subject results showed that more minutes spent in VPA the previous day was associated with shorter sleep duration the next night, whereas no effect was observed for MVPA. Longer sleep duration the previous night was associated with less MVPA but more VPA the next day. Neither MVPA nor VPA were associated with subsequent night's sleep quality, but better quality of sleep predicted more MVPA and VPA the next day. CONCLUSIONS: Sleep duration and PA are bi-directionally linked, but only for vigorous physical activity. More time spent in VPA shortens sleep the next night, yet longer sleep duration increases VPA the next day. The results imply that a 24-h framing for the interrelations of sleep and physical activity is not sufficient - the dynamics can even extend beyond, and are activated specifically for the links between sleep duration and vigorous activity. The results challenge the view that sleep quality can be improved by increasing the amount of PA. Yet, better sleep quality can result in more PA the next day.

Is It Time We Stop Discouraging Evening Physical Activity? New Real-World Evidence From 150,000 Nights.

Professional and colloquial sleep hygiene guidelines advise against evening physical activity, despite meta-analyses of laboratory studies concluding that evening exercise does not impair sleep. This study is the first to investigate the association between objectively measured evening physical activity and sleep within a real-world big-data sample. A total of 153,154 nights from 12,638 individuals aged 18-60 years (M = 40.1 SD = 10.1; 44.5% female) were analyzed. Nighttime sleep and minutes of physical activity were assessed using Polar wearable devices for 14 consecutive days. Thirty minutes or more of moderate-to-near maximal physical activity during the 3 h before sleep onset were recorded in 12.4% of evenings, and were more frequent on weekdays than weekends (13.3 vs. 10.2% respectively, p < 0.001). Linear mixed modeling revealed that sleep efficiency was not significantly associated with evening physical activity, and that sleep duration was 3.4 min longer on average on nights following evenings in which participants engaged in 30 min or more of moderate-intense physical activity. Effects were found for sleep timing metrics, as evening physical activity was linked with earlier sleep onset and offset times (-13.7 and -9.3 min, respectively). Overall, these effects were greater- but still very small- on weekdays compared to weekends. The present study provides further evidence for the lack of meaningful links between sleep duration or quality and physical activity in the hours preceding sleep. Taken together with recent meta-analytic findings, these findings suggest that changes in public health recommendations are warranted regarding evening physical activity and its relation to sleep.

Energy expenditure estimation from respiration variables.

The aim of this study was to develop and cross-validate two models to estimate total energy expenditure (TEE) based on respiration variables in healthy subjects during daily physical activities. Ninety-nine male and female subjects systematically varying in age (18-60 years) and body mass index (BMI; 17-36 kg*m-2) completed eleven aerobic activities with a portable spirometer as the criterion measure. Two models were developed using linear regression analyses with the data from 67 randomly selected subjects (50.0% female, 39.9 ± 11.8 years, 25.1 ± 5.2 kg*m-2). The models were cross-validated with the other 32 subjects (49% female, 40.4 ± 10.7 years, 24.7 ± 4.6 kg*m-2) by applying equivalence testing and Bland-and-Altman analyses. Model 1, estimating TEE based solely on respiratory volume, respiratory rate, and age, was significantly equivalent to the measured TEE with a systematic bias of 0.06 kJ*min-1 (0.22%) and limits of agreement of ±6.83 kJ*min-1. Model 1 was as accurate in estimating TEE as Model 2, which incorporated further information on activity categories, heart rate, sex, and BMI. The results demonstrated that respiration variables and age can be used to accurately determine daily TEE for different types of aerobic activities in healthy adults across a broad range of ages and body sizes.

Plenty of motion at the bottom: atomically thin liquid gold membrane.

The discovery of graphene some ten years ago was the first proof of a free-standing two-dimensional (2D) solid phase. Here, using quantum molecular dynamics simulations of nanoscale gold patches suspended in graphene pores, we predict the existence of an atomically thin, free-standing 2D liquid phase. The liquid phase, enabled by the exceptional planar stability of gold due to relativistic effects, demonstrates extreme fluxionality of metal nanostructures and opens possibilities for a variety of nanoscale phenomena.

Ca2+-calmodulin-dependent protein kinase II represses cardiac transcription of the L-type calcium channel alpha(1C)-subunit gene (Cacna1c) by DREAM translocation.

Recent studies have demonstrated that changes in the activity of calcium-calmodulin-dependent protein kinase II (CaMKII) induce a unique cardiomyocyte phenotype through the regulation of specific genes involved in excitation-contraction (E-C)-coupling. To explain the transcriptional effects of CaMKII we identified a novel CaMKII-dependent pathway for controlling the expression of the pore-forming α-subunit (Cav1.2) of the L-type calcium channel (LTCC) in cardiac myocytes. We show that overexpression of either cytosolic (δC) or nuclear (δB) CaMKII isoforms selectively downregulate the expression of the Cav1.2. Pharmacological inhibition of CaMKII activity induced measurable changes in LTCC current density and subsequent changes in cardiomyocyte calcium signalling in less than 24 h. The effect of CaMKII on the α1C-subunit gene (Cacna1c) promoter was abolished by deletion of the downstream regulatory element (DRE), which binds transcriptional repressor DREAM/calsenilin/KChIP3. Imaging DREAM-GFP (green fluorescent protein)-expressing cardiomyocytes showed that CaMKII potentiates the calcium-induced nuclear translocation of DREAM. Thereby CaMKII increases DREAM binding to the DRE consensus sequence of the endogenous Cacna1c gene. By mathematical modelling we demonstrate that the LTCC downregulation through the Ca2+-CaMKII-DREAM cascade constitutes a physiological feedback mechanism enabling cardiomyocytes to adjust the calcium intrusion through LTCCs to the amount of intracellular calcium detected by CaMKII.

Impact of sarcoplasmic reticulum calcium release on calcium dynamics and action potential morphology in human atrial myocytes: a computational study.

Electrophysiological studies of the human heart face the fundamental challenge that experimental data can be acquired only from patients with underlying heart disease. Regarding human atria, there exist sizable gaps in the understanding of the functional role of cellular Ca²+ dynamics, which differ crucially from that of ventricular cells, in the modulation of excitation-contraction coupling. Accordingly, the objective of this study was to develop a mathematical model of the human atrial myocyte that, in addition to the sarcolemmal (SL) ion currents, accounts for the heterogeneity of intracellular Ca²+ dynamics emerging from a structurally detailed sarcoplasmic reticulum (SR). Based on the simulation results, our model convincingly reproduces the principal characteristics of Ca²+ dynamics: 1) the biphasic increment during the upstroke of the Ca²+ transient resulting from the delay between the peripheral and central SR Ca²+ release, and 2) the relative contribution of SL Ca²+ current and SR Ca²+ release to the Ca²+ transient. In line with experimental findings, the model also replicates the strong impact of intracellular Ca²+ dynamics on the shape of the action potential. The simulation results suggest that the peripheral SR Ca²+ release sites define the interface between Ca²+ and AP, whereas the central release sites are important for the fire-diffuse-fire propagation of Ca²+ diffusion. Furthermore, our analysis predicts that the modulation of the action potential duration due to increasing heart rate is largely mediated by changes in the intracellular Na+ concentration. Finally, the results indicate that the SR Ca²+ release is a strong modulator of AP duration and, consequently, myocyte refractoriness/excitability. We conclude that the developed model is robust and reproduces many fundamental aspects of the tight coupling between SL ion currents and intracellular Ca²+ signaling. Thus, the model provides a useful framework for future studies of excitation-contraction coupling in human atrial myocytes.

Local Ca2+ releases enable rapid heart rates in developing cardiomyocytes.

The ability to generate homogeneous intracellular Ca(2+) oscillations at high frequency is the basis of the rhythmic contractions of mammalian cardiac myocytes. While the specific mechanisms and structures enabling homogeneous high-frequency Ca(2+) signals in adult cardiomyocytes are well characterized, it is not known how these kind of Ca(2+) signals are produced in developing cardiomyocytes. Here we investigated the mechanisms reducing spatial and temporal heterogeneity of cytosolic Ca(2+) signals in mouse embryonic ventricular cardiomyocytes. We show that in developing cardiomyocytes the propagating Ca(2+) signals are amplified in cytosol by local Ca(2+) releases. Local releases are based on regular 3-D sarcoplasmic reticulum (SR) structures containing SR Ca(2+) uptake ATPases (SERCA) and Ca(2+) release channels (ryanodine receptors, RyRs) at regular intervals throughout the cytosol. By evoking [Ca(2+)](i)-induced Ca(2+) sparks, the local release sites promote a 3-fold increase in the cytosolic Ca(2+) propagation speed. We further demonstrate by mathematical modelling that without these local release sites the developing cardiomyocytes lose their ability to generate homogeneous global Ca(2+) signals at a sufficiently high frequency. The mechanism described here is robust and indispensable for normal mammalian cardiomyocyte function from the first heartbeats during the early embryonic phase till terminal differentiation after birth. These results suggest that local cytosolic Ca(2+) releases are indispensable for normal cardiomyocyte development and function of developing heart.

Myogenic skeletal muscle satellite cells communicate by tunnelling nanotubes.

Quiescent satellite cells sit on the surface of the muscle fibres under the basal lamina and are activated by a variety of stimuli to disengage, divide and differentiate into myoblasts that can regenerate or repair muscle fibres. Satellite cells adopt their parent's fibre type and must have some means of communication with the parent fibre. The mechanisms behind this communication are not known. We show here that satellite cells form dynamic connections with muscle fibres and other satellite cells by F-actin based tunnelling nanotubes (TNTs). Our results show that TNTs readily develop between satellite cells and muscle fibres. Once developed, TNTs permit transport of intracellular material, and even cellular organelles such as mitochondria between the muscle fibre and satellite cells. The onset of satellite cell differentiation markers Pax-7 and MyoD expression was slower in satellite cells cultured in the absence than in the presence of muscle cells. Furthermore physical contact between myofibre and satellite cell progeny is required to maintain subtype identity. Our data establish that TNTs constitute an integral part of myogenic cell communication and that physical cellular interaction control myogenic cell fate determination.

Regulation of excitation-contraction coupling in mouse cardiac myocytes: integrative analysis with mathematical modelling.

BACKGROUND: The cardiomyocyte is a prime example of inherently complex biological system with inter- and cross-connected feedback loops in signalling, forming the basic properties of intracellular homeostasis. Functional properties of cells and tissues have been studied e.g. with powerful tools of genetic engineering, combined with extensive experimentation. While this approach provides accurate information about the physiology at the endpoint, complementary methods, such as mathematical modelling, can provide more detailed information about the processes that have lead to the endpoint phenotype. RESULTS: In order to gain novel mechanistic information of the excitation-contraction coupling in normal myocytes and to analyze sophisticated genetically engineered heart models, we have built a mathematical model of a mouse ventricular myocyte. In addition to the fundamental components of membrane excitation, calcium signalling and contraction, our integrated model includes the calcium-calmodulin-dependent enzyme cascade and the regulation it imposes on the proteins involved in excitation-contraction coupling. With the model, we investigate the effects of three genetic modifications that interfere with calcium signalling: 1) ablation of phospholamban, 2) disruption of the regulation of L-type calcium channels by calcium-calmodulin-dependent kinase II (CaMK) and 3) overexpression of CaMK. We show that the key features of the experimental phenotypes involve physiological compensatory and autoregulatory mechanisms that bring the system to a state closer to the original wild-type phenotype in all transgenic models. A drastic phenotype was found when the genetic modification disrupts the regulatory signalling system itself, i.e. the CaMK overexpression model. CONCLUSION: The novel features of the presented cardiomyocyte model enable accurate description of excitation-contraction coupling. The model is thus an applicable tool for further studies of both normal and defective cellular physiology. We propose that integrative modelling as in the present work is a valuable complement to experiments in understanding the causality within complex biological systems such as cardiac myocytes.

Modelling sarcoplasmic reticulum calcium ATPase and its regulation in cardiac myocytes.

When developing large-scale mathematical models of physiology, some reduction in complexity is necessarily required to maintain computational efficiency. A prime example of such an intricate cell is the cardiac myocyte. For the predictive power of the cardiomyocyte models, it is vital to accurately describe the calcium transport mechanisms, since they essentially link the electrical activation to contractility. The removal of calcium from the cytoplasm takes place mainly by the Na(+)/Ca(2+) exchanger, and the sarcoplasmic reticulum Ca(2+) ATPase (SERCA). In the present study, we review the properties of SERCA, its frequency-dependent and beta-adrenergic regulation, and the approaches of mathematical modelling that have been used to investigate its function. Furthermore, we present novel theoretical considerations that might prove useful for the elucidation of the role of SERCA in cardiac function, achieving a reduction in model complexity, but at the same time retaining the central aspects of its function. Our results indicate that to faithfully predict the physiological properties of SERCA, we should take into account the calcium-buffering effect and reversible function of the pump. This 'uncomplicated' modelling approach could be useful to other similar transport mechanisms as well.

Model of excitation-contraction coupling of rat neonatal ventricular myocytes.

The neonatal rat ventricular myocyte culture is one of the most popular experimental cardiac cell models. To our knowledge, the excitation-contraction coupling (ECC) of these cells, i.e., the process linking the electrical activity to the cytosolic Ca2+ transient and contraction, has not been previously analyzed, nor has it been presented as a complete system in detail. Neonatal cardiomyocytes are in the postnatal developmental stage, and therefore, the features of their ECC differ vastly from those of adult ventricular myocytes. We present the first complete analysis of ECC in these cells by characterizing experimentally the action potential and calcium signaling and developing the first mathematical model of ECC in neonatal cardiomyocytes that we know of. We show that in comparison to adult cardiomyocytes, neonatal cardiomyocytes have long action potentials, heterogeneous cytosolic Ca2+ signals, weaker sarcoplasmic reticulum Ca2+ handling, and stronger sarcolemmal Ca2+ handling, with a significant contribution by the Na+/Ca2+ exchanger. The developed model reproduces faithfully the ECC of rat neonatal cardiomyocytes with a novel description of spatial cytosolic [Ca2+] signals. Simulations also demonstrate how an increase in the cell size (hypertrophy) affects the ECC in neonatal cardiomyocytes. This model of ECC in developing cardiomyocytes provides a platform for developing future models of cardiomyocytes at different developmental stages.

Excitation-contraction coupling of the mouse embryonic cardiomyocyte.

In the mammalian embryo, the primitive tubular heart starts beating during the first trimester of gestation. These early heartbeats originate from calcium-induced contractions of the developing heart muscle cells. To explain the initiation of this activity, two ideas have been presented. One hypothesis supports the role of spontaneously activated voltage-gated calcium channels, whereas the other emphasizes the role of Ca(2+) release from intracellular stores initiating spontaneous intracellular calcium oscillations. We show with experiments that both of these mechanisms coexist and operate in mouse cardiomyocytes during embryonic days 9-11. Further, we characterize how inositol-3-phosphate receptors regulate the frequency of the sarcoplasmic reticulum calcium oscillations and thus the heartbeats. This study provides a novel view of the regulation of embryonic cardiomyocyte activity, explaining the functional versatility of developing cardiomyocytes and the origin and regulation of the embryonic heartbeat.

Mathematical model of mouse embryonic cardiomyocyte excitation-contraction coupling.

Excitation-contraction (E-C) coupling is the mechanism that connects the electrical excitation with cardiomyocyte contraction. Embryonic cardiomyocytes are not only capable of generating action potential (AP)-induced Ca(2+) signals and contractions (E-C coupling), but they also can induce spontaneous pacemaking activity. The spontaneous activity originates from spontaneous Ca(2+) releases from the sarcoplasmic reticulum (SR), which trigger APs via the Na(+)/Ca(2+) exchanger (NCX). In the AP-driven mode, an external stimulus triggers an AP and activates voltage-activated Ca(2+) intrusion to the cell. These complex and unique features of the embryonic cardiomyocyte pacemaking and E-C coupling have never been assessed with mathematical modeling. Here, we suggest a novel mathematical model explaining how both of these mechanisms can coexist in the same embryonic cardiomyocytes. In addition to experimentally characterized ion currents, the model includes novel heterogeneous cytosolic Ca(2+) dynamics and oscillatory SR Ca(2+) handling. The model reproduces faithfully the experimentally observed fundamental features of both E-C coupling and pacemaking. We further validate our model by simulating the effect of genetic modifications on the hyperpolarization-activated current, NCX, and the SR Ca(2+) buffer protein calreticulin. In these simulations, the model produces a similar functional alteration to that observed previously in the genetically engineered mice, and thus provides mechanistic explanations for the cardiac phenotypes of these animals. In general, this study presents the first model explaining the underlying cellular mechanism for the origin and the regulation of the heartbeat in early embryonic cardiomyocytes.