Understanding and Quantifying Molecular Flexibility: Torsion Angular Bin Strings.

Molecular flexibility is a commonly used, but not easily quantified term. It is at the core of understanding composition and size of a conformational ensemble and contributes to many molecular properties. For many computational workflows, it is necessary to reduce a conformational ensemble to meaningful representatives, however defining them and guaranteeing the ensemble's completeness is difficult.

Mild Cold Stress at Ambient Temperature Elevates Muscle Calcium Cycling and Exercise Adaptations in Obese Female Mice.

Context: Housing temperature is a critical regulator of mouse metabolism and thermoneutral housing can improve model translation to humans. However, the impact of housing temperature on the ability of wheel running exercise training to rescue the detrimental effect of diet-induced obese mice is currently not fully understood.

Objective: To investigate how housing temperature affects muscle metabolism in obese mice with regard to calcium handling and exercise training (ET) adaptations in skeletal muscle, and benefits of ET on adiposity and glucometabolic parameters.

lwreg: A Lightweight System for Chemical Registration and Data Storage.

Here, we present lwreg, a lightweight, yet flexible chemical registration system supporting the capture of both two-dimensional molecular structures (topologies) and three-dimensional conformers. lwreg is open source, with a simple Python API, and is designed to be easily integrated into computational workflows. In addition to lwreg itself, we also introduce a straightforward schema for storing experimental data and metadata in the registration database.

Spaceflight increases sarcoplasmic reticulum Ca leak and this cannot be counteracted with BuOE treatment.

Spending time in a microgravity environment is known to cause significant skeletal muscle atrophy and weakness via muscle unloading, which can be partly attributed to Ca dysregulation. The sarco(endo)plasmic reticulum Ca ATPase (SERCA) pump is responsible for bringing Ca from the cytosol into its storage site, the sarcoplasmic reticulum (SR), at the expense of ATP. We have recently demonstrated that, in the soleus of space-flown mice, the Ca uptake ability of the SERCA pump is severely impaired and this may be attributed to increases in reactive oxygen/nitrogen species (RONS), to which SERCA is highly susceptible.

Perimenopause Decreases SERCA2a Activity in the Hearts of a Mouse Model of Ovarian Failure.

Risk of cardiovascular disease mortality rises in women after menopause. While increased cardiovascular risk is largely attributed to postmenopausal declines in estrogens, the molecular changes in the heart that contribute to risk are poorly understood. Disruptions in intracellular calcium handling develop in ovariectomized mice and have been implicated in cardiac dysfunction.

Characterizing the effects of muscle-specific GSK3α/β reduction on murine muscle contractility and metabolism in female mice.

Dysregulation of skeletal muscle morphology and metabolism is associated with chronic diseases such as obesity and type 2 diabetes. The enzyme glycogen synthase kinase 3 (GSK3) is highly involved in skeletal muscle physiology and metabolism, acting as a negative regulator of muscle size, strength, adaptive thermogenesis, and glucose homeostasis. Correspondingly, we have shown that partial knockdown (∼40%) of GSK3 specifically in skeletal muscle increases lean mass, reduces fat mass, and activates muscle-based adaptive thermogenesis via sarco(endo)plasmic reticulum Ca (SERCA) uncoupling in male mice.

Parallel control of cold-triggered adipocyte thermogenesis by UCP1 and CKB.

That uncoupling protein 1 (UCP1) is the sole mediator of adipocyte thermogenesis is a conventional viewpoint that has primarily been inferred from the attenuation of the thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1). However, germline Ucp1 mice harbor secondary changes within brown adipose tissue. To mitigate these potentially confounding ancillary changes, we constructed mice with inducible adipocyte-selective Ucp1 disruption.

Explainable machine learning identifies multi-omics signatures of muscle response to spaceflight in mice.

The adverse effects of microgravity exposure on mammalian physiology during spaceflight necessitate a deep understanding of the underlying mechanisms to develop effective countermeasures. One such concern is muscle atrophy, which is partly attributed to the dysregulation of calcium levels due to abnormalities in SERCA pump functioning. To identify potential biomarkers for this condition, multi-omics data and physiological data available on the NASA Open Science Data Repository (osdr.

Toward countering muscle and bone loss with spaceflight: GSK3 as a potential target.

We examined the effects of ∼30 days of spaceflight on glycogen synthase kinase 3 (GSK3) content and inhibitory serine phosphorylation in murine muscle and bone samples from four separate missions (BION-M1, rodent research [RR]1, RR9, and RR18). Spaceflight reduced GSK3β content across all missions, whereas its serine phosphorylation was elevated with RR18 and BION-M1. The reduction in GSK3β was linked to the reduction in type IIA fibers commonly observed with spaceflight as these fibers are particularly enriched with GSK3.

Melanocortin 4 receptor signaling in Sim1 neurons permits sexual receptivity in female mice.

Introduction: Female sexual dysfunction affects approximately 40% of women in the United States, yet few therapeutic options exist for these patients. The melanocortin system is a new treatment target for hypoactive sexual desire disorder (HSDD), but the neuronal pathways involved are unclear.

Methods: In this study, the sexual behavior of female MC4R knockout mice lacking melanocortin 4 receptors (MC4Rs) was examined.

Acute activation of SERCA with CDN1163 attenuates IgE-mediated mast cell activation through selective impairment of ROS and p38 signaling.

Mast cells are granulocytic immune sentinels present in vascularized tissues that drive chronic inflammatory mechanisms characteristic of allergic pathologies. IgE-mediated mast cell activation leads to a rapid mobilization of Ca from intracellular stores, which is essential for the release of preformed mediators via degranulation and de novo synthesized proinflammatory cytokines and chemokines. Given its potent signaling capacity, the dynamics of Ca localization are highly regulated by various pumps and channels controlling cytosolic Ca concentrations.

Measuring SERCA-mediated calcium uptake in mouse muscle homogenates.

This protocol employs the indo-1 Ca fluorophore to quantify Ca uptake by the sarco(endo)plasmic reticulum Ca ATPase pump in murine muscle homogenates and allows for real-time kinetic measurement of Ca mobilization within the muscle homogenate. This protocol can be easily adapted for other tissue types and can be modified to single-emission/single-excitation Ca dyes. Fitted to a 96-well plate, this assay can be readily performed in most laboratories with minimal sample requirement and the option of multiple replicates.

Erratum: Corringendum: The effects of neurogranin knockdown on SERCA pump efficiency in soleus muscles of female mice fed a high fat diet.

[This corrects the article DOI: 10.3389/fendo.2022.

Low-dose lithium supplementation promotes adipose tissue browning and sarco(endo)plasmic reticulum Ca ATPase uncoupling in muscle.

Sarco(endo)plasmic reticulum Ca-ATPase (SERCA) uncoupling in skeletal muscle and mitochondrial uncoupling via uncoupling protein 1 (UCP1) in brown/beige adipose tissue are two mechanisms implicated in energy expenditure. Here, we investigated the effects of glycogen synthase kinase 3 (GSK3) inhibition via lithium chloride (LiCl) treatment on SERCA uncoupling in skeletal muscle and UCP1 expression in adipose. C2C12 and 3T3-L1 cells treated with LiCl had increased SERCA uncoupling and UCP1 protein levels, respectively, ultimately raising cellular respiration; however, this was only observed when LiCl treatment occurred throughout differentiation.

Sarco(endo)plasmic reticulum Ca-ATPase function is impaired in skeletal and cardiac muscles from young DBA/2J mdx mice.

The DBA/2J (D2) mouse is a more severe model of Duchenne muscular dystrophy when compared to the traditional C57BL/10 (C57) mouse. Here, we questioned whether sarco(endo)plasmic reticulum Ca-ATPase (SERCA) function would differ in muscles from young D2 and C57 mice. Both D2 and C57 mice exhibited signs of impaired Ca uptake in the gastrocnemius, diaphragm, and left ventricle; however, the level of impairment was more severe in D2 mice.

The effects of neurogranin knockdown on SERCA pump efficiency in soleus muscles of female mice fed a high fat diet.

The sarco(endo)plasmic reticulum Ca ATPase (SERCA) pump is responsible for the transport of Ca from the cytosol into the sarcoplasmic reticulum at the expense of ATP, making it a regulator of both muscle relaxation and muscle-based energy expenditure. Neurogranin (Ng) is a small protein that negatively regulates calcineurin signaling. Calcineurin is Ca/calmodulin dependent phosphatase that promotes the oxidative fibre type in skeletal muscle and regulates muscle-based energy expenditure.

Neurogranin inhibits calcineurin in murine soleus muscle: Effects of heterozygous knockdown on muscle adaptations to tenotomy and fatigue resistance.

Neurogranin (Ng) is a calmodulin (CaM) binding protein that negatively regulates calcineurin - a Ca/CaM-dependent phosphatase that can mitigate the slow-to-fast fibre type shift observed with muscle unloading. Here, we questioned whether heterozygous deletion of Ng (Ng) would enhance calcineurin activity, thereby minimizing the slow-to-fast fibre type shift caused by muscle unloading. As expected, soleus muscles from young adult (3-4 months old) Ng mice had lowered Ng content and enhanced calcineurin activity when compared to soleus muscles obtained from male age-matched wild-type (WT) mice.

Mapping of Protein Binding Sites using clustering algorithms - Development of a pharmacophore based drug discovery tool.

Discovering new hit small molecules binding to a specific protein binding site can be a difficult task. In support of existing procedures, a proof of concept methodology has been developed to process fragment flooded X-ray protein structures using the K-means clustering algorithm in order to derive pharmacophore models of the binding site. The novel method includes the implementation of several K-means initialisation methods in serial and parallel versions.

Heterozygous SOD2 deletion selectively impairs SERCA function in the soleus of female mice.

The sarco(endo)plasmic reticulum Ca ATPase (SERCA) restores intracellular Ca ([Ca ] ) to resting levels after muscle contraction, ultimately eliciting relaxation. SERCA pumps are highly susceptible to tyrosine (T)-nitration, impairing their ability to take up Ca resulting in reduced muscle function and increased [Ca ] and cellular damage. The mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2), converts superoxide radicals into less reactive H O .

Characterizing SERCA Function in Murine Skeletal Muscles after 35-37 Days of Spaceflight.

It is well established that microgravity exposure causes significant muscle weakness and atrophy via muscle unloading. On Earth, muscle unloading leads to a disproportionate loss in muscle force and size with the loss in muscle force occurring at a faster rate. Although the exact mechanisms are unknown, a role for Ca dysregulation has been suggested.

Neuronatin promotes SERCA uncoupling and its expression is altered in skeletal muscles of high-fat diet-fed mice.

Neuronatin (NNAT) is a transmembrane protein in the endoplasmic reticulum involved in metabolic regulation. It shares sequence homology with sarcolipin (SLN), which negatively regulates the sarco(endo)plasmic reticulum Ca -ATPase (SERCA) that maintains energy homeostasis in muscles. Here, we examined whether NNAT could uncouple the Ca transport activity of SERCA from ATP hydrolysis, similarly to SLN.

Neuronatin regulates whole-body metabolism: is thermogenesis involved?

Neuronatin (NNAT) was originally discovered in 1995 and labeled as a brain developmental gene due to its abundant expression in developing brains. Over the past 25 years, researchers have uncovered NNAT in other tissues; notably, the hypothalamus, pancreatic β-cells, and adipocytes. Recent evidence in these tissues indicates that NNAT plays a significant role in metabolism whereby it regulates food intake, insulin secretion, and adipocyte differentiation.

The role of phospholamban and GSK3 in regulating rodent cardiac SERCA function.

Cardiac contractile function is largely mediated by the regulation of Ca cycling throughout the lifespan. The sarco(endo)plasmic reticulum Ca ATPase (SERCA) pump is paramount to cardiac Ca regulation, and it is well established that SERCA dysfunction pathologically contributes to cardiomyopathy and heart failure. Phospholamban (PLN) is a well-known inhibitor of the SERCA pump and its regulation of SERCA2a-the predominant cardiac SERCA isoform-contributes significantly to proper cardiac function.