Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current,
, underlies exercise training-induced sinus ...bradycardia in rodents. If this occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran athletes, and it will be important to understand the underlying processes.
To test the role of HCN4 in the training-induced bradycardia in human athletes and investigate the role of microRNAs (miRs) in the repression of HCN4.
As in rodents, the intrinsic heart rate was significantly lower in human athletes than in nonathletes, and in all subjects, the rate-lowering effect of the HCN selective blocker, ivabradine, was significantly correlated with the intrinsic heart rate, consistent with HCN repression in athletes. Next-generation sequencing and quantitative real-time reverse transcription polymerase chain reaction showed remodeling of miRs in the sinus node of swim-trained mice. Computational predictions highlighted a prominent role for miR-423-5p. Interaction between miR-423-5p and HCN4 was confirmed by a dose-dependent reduction in HCN4 3'-untranslated region luciferase reporter activity on cotransfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements). Knockdown of miR-423-5p with anti-miR-423-5p reversed training-induced bradycardia via rescue of HCN4 and
. Further experiments showed that in the sinus node of swim-trained mice, upregulation of miR-423-5p (intronic miR) and its host gene, NSRP1, is driven by an upregulation of the transcription factor Nkx2.5.
HCN remodeling likely occurs in human athletes, as well as in rodent models. miR-423-5p contributes to training-induced bradycardia by targeting HCN4. This work presents the first evidence of miR control of HCN4 and heart rate. miR-423-5p could be a therapeutic target for pathological sinus node dysfunction in veteran athletes.
Heart failure is a multifactorial disease that affects an estimated 38 million people worldwide. Current pharmacotherapy of heart failure with reduced ejection fraction (HFrEF) includes combination ...therapy with angiotensin-converting enzyme inhibitors (ACEi) and β-adrenergic receptor blockers (β-AR blockers), a therapy also used as treatment for non-cardiac conditions. Our knowledge of the molecular changes accompanying treatment with ACEi and β-AR blockers is limited. Here, we applied proteomics and phosphoproteomics approaches to profile the global changes in protein abundance and phosphorylation state in cardiac left ventricles consequent to combination therapy of β-AR blocker and ACE inhibitor in HFrEF and control hearts. The phosphorylation changes induced by treatment were profoundly different for failing than for non-failing hearts. HFrEF was characterized by profound downregulation of mitochondrial proteins coupled with derangement of β-adrenergic and pyruvate dehydrogenase signaling. Upon treatment, phosphorylation changes consequent to HFrEF were reversed. In control hearts, treatment mainly led to downregulation of canonical PKA signaling. The observation of divergent signaling outcomes depending on disease state underscores the importance of evaluating drug effects within the context of the specific conditions present in the recipient heart.
A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome ...sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10
). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10
). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.
The sinus node is a collection of highly specialised cells constituting the heart's pacemaker. The molecular underpinnings of its pacemaking abilities are debated. Using high-resolution mass ...spectrometry, we here quantify >7,000 proteins from sinus node and neighbouring atrial muscle. Abundances of 575 proteins differ between the two tissues. By performing single-nucleus RNA sequencing of sinus node biopsies, we attribute measured protein abundances to specific cell types. The data reveal significant differences in ion channels responsible for the membrane clock, but not in Ca
clock proteins, suggesting that the membrane clock underpins pacemaking. Consistently, incorporation of ion channel expression differences into a biophysically-detailed atrial action potential model result in pacemaking and a sinus node-like action potential. Combining our quantitative proteomics data with computational modeling, we estimate ion channel copy numbers for sinus node myocytes. Our findings provide detailed insights into the unique molecular make-up of the cardiac pacemaker.
Delineating human cardiac pathologies and their basic molecular mechanisms relies on research conducted in model organisms. Yet translating findings from preclinical models to humans present a ...significant challenge, in part due to differences in cardiac protein expression between humans and model organisms. Proteins immediately determine cellular function, yet their large-scale investigation in hearts has lagged behind those of genes and transcripts. Here, we set out to bridge this knowledge gap: By analyzing protein profiles in humans and commonly used model organisms across cardiac chambers, we determine their commonalities and regional differences. We analyzed cardiac tissue from each chamber of human, pig, horse, rat, mouse, and zebrafish in biological replicates. Using mass spectrometry-based proteomics workflows, we measured and evaluated the abundance of approximately 7,000 proteins in each species. The resulting knowledgebase of cardiac protein signatures is accessible through an online database: atlas.cardiacproteomics.com. Our combined analysis allows for quantitative evaluation of protein abundances across cardiac chambers, as well as comparisons of cardiac protein profiles across model organisms. Up to a quarter of proteins with differential abundances between atria and ventricles showed opposite chamber-specific enrichment between species; these included numerous proteins implicated in cardiac disease. The generated proteomics resource facilitates translational prospects of cardiac studies from model organisms to humans by comparisons of disease-linked protein networks across species.
The responses of forest carbon dynamics to fluctuations in environmental conditions at a global scale remain elusive. Despite the understanding that favourable environmental conditions promote forest ...growth, these responses have been challenging to observe across different ecosystems and climate gradients. Based on a global annual time series of aboveground biomass (AGB) estimated from radar satellites between 1992 and 2018, we present forest carbon changes and provide insights on their sensitivities to environmental conditions across scales. Our findings indicate differences in forest carbon changes across AGB classes, with regions with carbon stocks of 50–125 MgC ha−1 depict the highest forest carbon gains and losses, while regions with 125–150 MgC ha−1 have the lowest forest carbon gains and losses in absolute terms. Net forest carbon change estimates show that the arc‐of‐deforestation and the Congo Basin were the main hotspots of forest carbon loss, while a substantial part of European forest gained carbon during the last three decades. Furthermore, we observe that changes in forest carbon stocks were systematically positively correlated with changes in forest cover fraction. At the same time, it was not necessarily the case with other environmental variables, such as air temperature and water availability at the bivariate level. We also used a model attribution method to demonstrate that atmospheric conditions were the dominant control of forest carbon changes (56% of the total study area) followed by water‐related (29% of the total study area) and vegetation (15% of the total study area) conditions. Regionally, we find evidence that carbon gains from long‐term forest growth covary with long‐term carbon sinks inferred from atmospheric inversions. Our results describe the contributions from the atmosphere, water‐related and vegetation conditions to forest carbon changes and provide new insights into the underlying mechanisms of the coupling between forest growth and the global carbon cycle.
In this study, we use a novel record of global satellite‐derived estimates of aboveground biomass (AGB) spanning almost three decades to explore the global sensitivities of forest carbon changes to environmental conditions. We report on the spatial patterns of net forest carbon changes at a global scale and how forest carbon changes are modulated by climate, water‐related (e.g. soil moisture) and vegetation conditions (e.g. LAI, NDVI and GPP) across scales. Furthermore, we investigate regionally whether carbon gains from long‐term forest growth were coupled with long‐term carbon sinks inferred from atmospheric inversion.
Abstract The impact of spring climate on the Northern Hemisphere's summer vegetation activity and extremes has been extensively researched, but less attention has been devoted to whether and how ...winter climate may additionally influence vegetation extremes in summer. Here, we provide insights into the influence of winter temperature and precipitation on summer vegetation extremes in the Northern Hemisphere. To do this, we identify positive and negative extremes in the summer Leaf Area Index (LAI, a proxy for vegetation activity) and assess winter effects on those extremes using logistic regression at the regional scale. Over a quarter of the regions in the Northern Hemisphere show strong winter climate preconditioning on summer LAI extremes, which is typically stronger for croplands than forests. In the regions with strong winter preconditioning, spring LAI mediates the link between winter climate and summer LAI extremes through the ecological memory in seasonal legacy effects. Our findings suggest that extremely low summer LAI in both croplands and forests is preconditioned by colder and drier winters, while extremely high summer LAI in forests is associated with warmer and wetter winters. For low summer LAI in croplands, warmer winters are associated with an increased likelihood of extremes in mid-latitude regions and a reduced likelihood in high latitude regions. Consideration of winter preconditioning effects may improve understanding of inter-annual variability of vegetation activity and support agricultural and land management practitioners in anticipating detrimental effects of winter on crop yields and forest conditions.
Proteomes were measured from human heart biopsies from right atria, left atria and left ventricle of seven male patients with mitral valve regurgitation at a depth of ∼7000 proteins. Results were ...confirmed in an independent set of biopsies from three individuals. Comparative analysis against data from post-mortem samples showed greatly enhanced quantitative power and confidence level in samples collected from living hearts. Our analysis, combined with data from genome wide association studies, suggest candidate gene associations to mitral valve prolapse.
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Highlights
•Proteomes measured from human heart biopsies collected in-vivo covers >7000 cardiac proteins and highlight hundreds of chamber-specific molecular signatures that meaningfully reflect the specialized functions of the respective chambers.•Protein quantification from freshly collected biopsies is preferential to necropsy samples because of unspecific post-mortem protein degradation in the latter.•Increased abundances of proteins associated with sustained atrial fibrillation are not a sufficient condition to generate the disease state.•Protein abundance differences between atria and ventricle primarily originate at the level of gene regulation and reflect a functional need.
Genetic and genomic research has greatly advanced our understanding of heart disease. Yet, comprehensive, in-depth, quantitative maps of protein expression in hearts of living humans are still lacking. Using samples obtained during valve replacement surgery in patients with mitral valve prolapse (MVP), we set out to define inter-chamber differences, the intersect of proteomic data with genetic or genomic datasets, and the impact of left atrial dilation on the proteome of patients with no history of atrial fibrillation (AF).
We collected biopsies from right atria (RA), left atria (LA) and left ventricle (LV) of seven male patients with mitral valve regurgitation with dilated LA but no history of AF. Biopsy samples were analyzed by high-resolution mass spectrometry (MS), where peptides were pre-fractionated by reverse phase high-pressure liquid chromatography prior to MS measurement on a Q-Exactive-HF Orbitrap instrument. We identified 7,314 proteins based on 130,728 peptides. Results were confirmed in an independent set of biopsies collected from three additional individuals. Comparative analysis against data from post-mortem samples showed enhanced quantitative power and confidence level in samples collected from living hearts. Our analysis, combined with data from genome wide association studies suggested candidate gene associations to MVP, identified higher abundance in ventricle for proteins associated with cardiomyopathies and revealed the dilated LA proteome, demonstrating differential representation of molecules previously associated with AF, in non-AF hearts.
This is the largest dataset of cardiac protein expression from human samples collected in vivo. It provides a comprehensive resource that allows insight into molecular fingerprints of MVP and facilitates novel inferences between genomic data and disease mechanisms. We propose that over-representation of proteins in ventricle is consequent not to redundancy but to functional need, and conclude that changes in abundance of proteins known to associate with AF are not sufficient for arrhythmogenesis.
Climate variables carry signatures of variability at multiple timescales. How these modes of variability are reflected in the state of the terrestrial biosphere is still not quantified or discussed ...at the global scale. Here, we set out to gain a global understanding of the relevance of different modes of variability in vegetation greenness and its covariability with climate. We used 30 years of remote sensing records of the normalized difference vegetation index (NDVI) to characterize biosphere variability across timescales from submonthly oscillations to decadal trends using discrete Fourier decomposition. Climate data of air temperature (T.sub.air) and precipitation (Prec) were used to characterize atmosphere-biosphere covariability at each timescale.
Much uncertainty remains in measuring the inter‐annual and longer‐term dynamics of vegetation gross and net primary productivity (GPP, NPP) and the connected land carbon sink. Potential for better ...GPP estimation lies in newer satellite products representing different processes or vegetation states, but how they capture interannual GPP dynamics remains to be explored. Here, we differentiate shorter‐ and longer‐term vegetation dynamics and their drivers for several Earth‐observation‐based vegetation proxies and a GPP estimate using time series decomposition. We find that relations between proxies can significantly differ between time scales, along land cover and climate gradients. For GPP estimated at FLUXNET sites, seasonal and multiannual slopes differ by at least 25% for half of the cases investigated, indicating considerable mismatch if multiannual relations were derived from seasonal slopes. Considering time‐scale‐specific sensitivities between proxies of vegetation productivity may improve estimates of interannual variability in vegetation productivity.
Plain Language Summary
How ecosystems will develop in the future is still difficult to predict, in part because the factors that influence ecosystems over several years or decades may differ from those influencing them in the course of a day or a year. Several satellites monitor vegetation growth on Earth and report, for example, leaf greenness or fluorescence. Fluorescence is often superior in tracking seasonal vegetation dynamics, but when it comes to understanding the long‐term imprint of climate, it remains to be clarified how different data products relate to each other. In this study, we compare how much changes in interannual and longer vegetation activity are captured by different satellite products. We find that the relationship between satellite proxies for vegetation differs between monthly, yearly and long‐term scales. These findings may help to better understand and predict vegetation growth and carbon uptake from the atmosphere in the future.
Key Points
Contrary to seasonal time scales, it is poorly understood how different vegetation productivity proxies relate at interannual time scales
Interannual relations between vegetation proxies need to be considered: Seasonal relations do not generally hold at multiannual scale
Time‐scale‐specific slopes between vegetation proxies vary along gradients of tree cover, vegetation type, climate, and across FLUXNET sites
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