A5085445693- Cardiomyopathy and Myosin Studies
- Muscle Physiology and Disorders
- Respiratory Support and Mechanisms
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Neurogenetic and Muscular Disorders Research
- Cellular Mechanics and Interactions
- Genetic Neurodegenerative Diseases
- Intensive Care Unit Cognitive Disorders
- Cardiovascular Effects of Exercise
- Cardiovascular Function and Risk Factors
- Pulmonary Hypertension Research and Treatments
- Congenital Diaphragmatic Hernia Studies
- Neuroscience of respiration and sleep
- Neonatal Respiratory Health Research
- Nutrition and Health in Aging
- Inflammatory Myopathies and Dermatomyositis
- Cardiovascular and exercise physiology
- Mitochondrial Function and Pathology
- Nuclear Structure and Function
- Microtubule and mitosis dynamics
- Muscle activation and electromyography studies
- Connective tissue disorders research
- Cardiac Arrest and Resuscitation
- Cystic Fibrosis Research Advances
- Congenital heart defects research
Amsterdam University Medical Centers
2019-2025
Amsterdam UMC Location VUmc
2014-2024
Inserm
2013-2024
University of Arizona
2015-2024
Radboud University Nijmegen
2005-2024
University Medical Center
2010-2024
Vrije Universiteit Amsterdam
2013-2024
Radboud University Medical Center
2005-2024
Assistance Publique – Hôpitaux de Paris
2024
Institut Mondor de Recherche Biomédicale
2024
Background— The role of right ventricular (RV) diastolic stiffness in pulmonary arterial hypertension (PAH) is not well established. Therefore, we investigated the presence and possible underlying mechanisms RV PAH patients. Methods Results— Single-beat pressure-volume analyses were performed 21 patients 7 control subjects to study stiffness. Data are presented as mean±SEM. (β) was significantly increased (PAH, 0.050±0.005 versus control, 0.029±0.003; P <0.05) closely associated with...
Background— Obesity and diabetes mellitus are important metabolic risk factors frequent comorbidities in heart failure with preserved ejection fraction. They contribute to myocardial diastolic dysfunction (DD) through collagen deposition or titin modification. The relative importance for DD of modification was investigated obese, diabetic ZSF1 rats after fraction development at 20 weeks. Methods Results— Four groups (Wistar-Kyoto, n=11; lean ZSF1, obese n=11, high-fat diet, n=11) were...
Mechanical ventilation can cause acute diaphragm atrophy and injury, this is associated with poor clinical outcomes. Although the importance impact of lung-protective widely appreciated well established, concept diaphragm-protective has recently emerged as a potential complementary therapeutic strategy. This Perspective, developed from discussions at meeting international experts convened by PLUG (the Pleural Pressure Working Group) European Society Intensive Care Medicine, outlines...
Rationale: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity duration hospital stay. To date, the nature its underlying pathophysiologic mechanisms are poorly understood.Objectives: We hypothesized that muscle fibers mechanically ventilated display atrophy contractile weakness, ubiquitin–proteasome pathway activated diaphragm.Methods: obtained biopsies from 22 who received mechanical ventilation...
Rationale: Hypercapnic respiratory failure because of inspiratory muscle weakness is the most important cause death in chronic obstructive pulmonary disease (COPD). However, pathophysiology diaphragm to generate force COPD part unclear. Objectives: The present study investigated contractile function and myosin heavy chain content single fibers from patients with COPD. Methods: Skinned were isolated biopsies eight mild moderate five without (mean FEV1 % predicted, 70 100%, respectively)....
Nemaline myopathy (NM) is a genetic muscle disorder characterized by dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described 9 genes to date, but the basis remains unknown many cases. Here, using an approach that combined whole-exome sequencing (WES) Sanger sequencing, we identified homozygous or compound heterozygous variants LMOD3 21 patients from 14 families with severe, usually lethal, NM. encodes leiomodin-3 (LMOD3),...
Inspiratory muscle weakness in patients with COPD is of major clinical relevance. For instance, maximum inspiratory pressure generation an independent determinant survival severe COPD. Traditionally, has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation contractile function, structure, and biochemistry demonstrated that cellular molecular alterations occur, which several can be considered pathologic nature. Whereas the fiber type shift...
Nemaline myopathy (NM) is the most common non-dystrophic congenital myopathy.Clinically important feature of NM muscle weakness; however, mechanisms underlying this weakness are poorly understood.Here, we studied muscular phenotype patients with a well-defined nebulin mutation (NM-NEB), using multidisciplinary approach to study thin filament length regulation and contractile performance.SDS -PAGE western blotting revealed greatly reduced levels in skeletal NM-NEB patients, prominent...
Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of in novel mouse model with genetically altered splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography.Compliant upregulated through deletion RNA...
The purpose of this study was to determine the relative contribution fibrosis-mediated and myofibril-mediated stiffness in rats with mild severe right ventricular (RV) dysfunction.By performing pulmonary artery banding different diameters for 7 weeks, RV dysfunction (Ø=0.6 mm) (Ø=0.5 were induced rats. fibrosis- determined trabecular strips. Total myocardial increased trabeculae from both comparison controls. In dysfunction, explained by stiffness, whereas only control. Histological analyses...
risk adults living with such workers.One limitation is that the study's prepandemic data do not reflect current employment levels, changes in ability to WAH, or local infection rates.Additionally, factors were reported by MEPS participants rather than measured medical professionals, likely causing an underestimate of risk.Policy makers seeking make efficient and equitable decisions about reopening economy vaccine distribution should consider health risks only workers, but also those whom they live.
Studies show that the myosin content of diaphragm in patients with mild to moderate chronic obstructive pulmonary disease (COPD) is reduced, compromising contractile performance. The mechanisms for reduced protein are unknown. In present study we hypothesized loss associated activation ubiquitin-proteasome pathway COPD.Proteolytic activity isolated 20S proteasomes was determined biopsies from and without COPD (predicted mean FEV1, 66 93%, respectively). addition, proteasome subunit C8 levels...
Nebulin is a giant filamentous F-actin-binding protein ( approximately 800 kDa) that binds along the thin filament of skeletal muscle sarcomere. one least well understood major proteins. Although nebulin usually viewed as structural protein, here we investigated whether plays role in contraction by using skinned fiber bundles from knock-out (NEB KO) mouse model. We measured force-pCa (-log[Ca(2+)]) and force-ATPase relations, rate tension re-development (k(tr)) tibialis cranialis fibers. To...
Limb-girdle muscular dystrophy type 2A (LGMD2A) is a genetic disease that caused by mutations in the calpain 3 gene (CAPN3), which encodes skeletal muscle-specific calpain, (also known as p94). However, precise mechanism p94 functions pathogenesis of this remains unclear. Here, using knockin mice (termed herein p94KI mice) endogenous was replaced with proteolytically inactive but structurally intact p94:C129S mutant protein, we have demonstrated stretch-dependent distribution sarcomeres...
Rationale: Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay increases mortality healthcare costs. The mechanisms underlying diaphragm include cross-sectional fiber atrophy contractile protein dysfunction, but whether additional are at play is unknown.Objectives: To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal by displacing caudal direction reducing length...
Nemaline myopathy (NM) is a rare congenital characterised by hypotonia, muscle weakness, and often skeletal deformities with the presence of nemaline bodies (rods) in biopsy. The nebulin (NEB) gene most commonly mutated thought to account for approximately 50% genetically diagnosed cases NM. We undertook detailed morphological analysis 14 NEB-mutated NM patients different clinical forms define pathological patterns correlate them course genotype. Three groups were identified according...
Titin, the largest protein known, forms an elastic myofilament in striated muscle sarcomere. To establish titin’s contribution to skeletal passive stiffness, relative that of extracellular matrix, a mouse model was created which molecular spring region shortened by deleting 47 exons, TtnΔ112-158 model. RNA sequencing and super-resolution microscopy predicts much stiffer titin molecule. Mechanical studies with this novel support is main determinant stiffness. Unexpectedly, vivo sarcomere...
Background Right ventricular ( RV ) diastolic function is impaired in patients with pulmonary arterial hypertension PAH ). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca 2+ sensitivity underlie dysfunction . This investigates protein modifications contributing to cellular Methods Results samples from undergoing heart‐lung transplantation were compared non‐failing donors (Don). Titin contribution was determined by Western‐blot analyses using antibodies...
The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency and increases morbidity, duration hospital stay, health care costs. mechanisms underlying are unknown, but might include mitochondrial dysfunction oxidative stress.We hypothesized that muscle fibers accompanied by impaired function structure, increased markers stress.To test these hypotheses, we studied contractile force, function, structure fibers. Fibers were isolated...
Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and caused by mutations in genes encoding proteins that associated with skeletal muscle thin filament. Mechanisms underlying weakness poorly understood, but might involve length of filament, an important determinant force generation.We investigated sarcomere length-dependence force, a functional assay provides insights into contractile strength fibers as well filaments, from 51 patients myopathy...