Rob C I Wüst

Vrije Universiteit Amsterdam | VU · Faculty of Human Movement Sciences

Background: Patients with multiple sclerosis (MS) experience reduced exercise tolerance that substantially reduces quality of life. The mechanisms underpinning exercise intolerance in MS are not fully clear. This study aimed to determine the contributions of the cardiopulmonary system and peripheral muscle in MS-induced exercise intolerance before...

Background: Systemic inflammation is associated with skeletal muscle atrophy and metabolic dysfunction. Although the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to cytokine production in immune cells, its role in skeletal muscle is poorly understood. Here, we studied the...

Mitochondria both sense biochemical and energetic input in addition to communicating signals regarding the energetic state of the cell. Increasingly, these signaling organelles are key for regulating different cell functions. This review summarizes recent advances in mitochondrial communication in striated muscle, with specific focus on the process...

Insulin sensitivity and metabolic flexibility decrease in response to bed rest, but the temporal and causal adaptations in human skeletal muscle metabolism are not fully defined. Here, we use an integrative approach to assess human skeletal muscle metabolism during bed rest and provide a multi-system analysis of how skeletal muscle and the circulat...

A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With th...

Intramuscular injection of botulinum neurotoxin type A (BoNT‐A) is commonly used to improve or maintain the joint range of motion in young children with spasticity. However, the effectiveness of BoNT‐A treatment is variable and movement limitations are recurrent. Here we show long‐term effects of a single, bilateral abobotulinumtoxinA (aboBoNT‐A) i...

Ageing substantially impairs skeletal muscle metabolic and physical function. Skeletal muscle mitochondrial health is also impaired with ageing, but the role of skeletal muscle mitochondrial fragmentation in age‐related functional decline remains imprecisely characterized. Here, using a cross‐sectional study design, we performed a detailed comparis...

Transforming growth factor-β (TGF-β) signaling is associated with progressive skeletal muscle wasting and fibrosis, while double knockout of TGF-β type I receptors Acvr1b and Tgfbr1 results in hypertrophy. Gaining insights in how myofibre-specific knockout of these receptors affects muscle transcriptome, strength and mitochondrial activity could ai...

Simultaneous inhibition of transforming growth factor-β (TGF-β) type I receptors Acvr1b and Tgfbr1 signalling has been associated with excessive skeletal muscle hypertrophy in vivo. However, it remains unclear whether the increased muscle mass in vivo is a direct result of inhibition of intracellular TGF-β signalling or whether this is an indirect...

SARS-CoV-2 infections worldwide led to a surge in cases of Long COVID, a post-infectious syndrome. It has been hypothesized that autoantibodies play a crucial role in the development of Long COVID and other syndromes, such as fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, we tested this hypothesis by pa...

Aims Active cigarette smoking is a major risk factor for chronic obstructive pulmonary disease that remains elevated after cessation. Skeletal muscle dysfunction has been well documented after smoking, but little is known about cardiac adaptations to cigarette smoking. The underlying cellular and molecular cardiac adaptations, independent of confou...

Patients with post- COVID condition suffer from fatigue, limited exercise capacity, and post-exertional malaise. Post-exertional malaise is the worsening of symptoms after physical or mental exertion, which reduces the efficacy of most forms of rehabilitation. This article presents the current understanding in the pathophysiology of post-COVID cond...

Background Many sports require maximal strength and endurance performance. Concurrent strength and endurance training can lead to suboptimal training adaptations. However, how adaptations differ between males and females is currently unknown. Additionally, current training status may affect training adaptations. Objective We aimed to assess sex-sp...

Study question: Are human ovarian aging and the age-related female fertility decline caused by oxidative stress and mitochondrial dysfunction in oocytes? Summary answer: We found oxidative damage in oocytes of advanced maternal age, even at the primordial follicle stage, and confirmed mitochondrial dysfunction in such oocytes, which likely resul...

Cigarette smoking is associated with a lower exercise capacity and lower muscle fatigue resistance. This is at least partly attributable to carboxyhaemoglobin (HbCO) in the blood that via reduction in the oxygen-carrying capacity, and the left-shift of the Hb-dissociation curve would reduce tissue oxygenation. On the other hand, a reduced oxygen up...

Earlier studies indicated that the degradation of tryptophan to kynurenine and further breakdown products. Rather than IDO1, our immunohistochemical analyses of lung, heart, brain and blood cells from patients with fatal/severe COVID-19 showed extensive expression and activity of the otherwise rarely expressed IDO2. This was associated with reduced...

Introduction: The antibiotic doxycycline is known to inhibit inflammation, and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. However, in two clinical trials, doxycycline-treated AAA patients did not experience reduced aneurysm growth. Doxycycline was previously shown to induce mitonuclear imbalance and...

Background Mobility is a key determinant and outcome of healthy ageing but its definition, conceptual framework and underlying constructs within the physical domain may need clarification for data comparison and sharing in ageing research. This study aimed to (1) review definitions and conceptual frameworks of mobility, (2) explore agreement on the...

The observation that prior heavy or severe-intensity exercise speeds overall oxygen uptake ([Formula: see text]O2) kinetics, termed the "priming effect", has garnered significant research attention and its underpinning mechanisms have been hotly debated. In the first part of this review, the evidence for and against (1) lactic acidosis, (2) increas...

Aims: Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mi...

Nicotinamide adenine dinucleotide (NAD+) is an evolutionarily highly conserved coenzyme with multi‐faceted cell functions, including energy metabolism, molecular signaling processes, epigenetic regulation, and DNA repair. Since the discovery that lower NAD+ levels are a shared characteristic of various diseases and ageing per se, several NAD+‐boost...

Ion fluxes across the inner mitochondrial membrane control mitochondrial volume, energy production, and apoptosis. TMBIM5, a highly conserved protein with homology to putative pH-dependent ion channels, is involved in the maintenance of mitochondrial cristae architecture, ATP production, and apoptosis. Here, we demonstrate that overexpressed TMBIM5...

Trabecular myocardium makes up most of the ventricular wall of the human embryo. A process of compaction in the foetal period presumably changes ventricular wall morphology by converting ostensibly weaker trabecular myocardium into stronger compact myocardium. Using developmental series of embryonic and foetal human, mouse and chicken, we show vent...

Background Muscle disuse from bed rest or spaceflight results in losses in muscle mass, strength and oxidative capacity. Capillary rarefaction may contribute to muscle atrophy and the reduction in oxidative capacity during bed rest. Artificial gravity may attenuate the negative effects of long‐term space missions or bed rest. The aim of the present...

To longitudinally assess left ventricle (LV) global longitudinal strain (GLS) and hemodynamic forces during the early stages of cardiac dysfunction in a mouse model of heart failure with preserved ejection fraction (HFpEF). Cardiac MRI measurements were performed in control mice (n = 6), and db/db mice (n = 7), whereby animals were scanned four tim...

Shift‐workers show an increased incidence of type 2 diabetes mellitus (T2DM). A possible mechanism is the disruption of the circadian timing of glucose homeostasis. Skeletal muscle mitochondrial function is modulated by the molecular clock. We used time‐restricted feeding (TRF) during the inactive phase to investigate how mistimed feeding affects m...

Skeletal muscle-related symptoms are common in both acute coronavirus disease (Covid)-19 and post-acute sequelae of Covid-19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, crit...

Despite decennia of research and numerous successful interventions in the preclinical setting, renal ischemia reperfusion (IR) injury remains a major problem in clinical practice, pointing towards a translational gap. Recently, two clinical studies on renal IR injury (manifested either as acute kidney injury or as delayed graft function), identifie...

Cigarette smoking has a negative effect on respiratory and skeletal muscle function and is a risk factor for various chronic diseases. To assess the effects of 14 days of smoking cessation on respiratory and skeletal muscle function, markers of inflammation and oxidative stress in humans. Spirometry, skeletal muscle function, circulating carboxyhae...

Trabecular muscle makes up most of the ventricular wall of the human embryo. It is presumed that compaction in the foetal period changes ventricular wall morphology by converting weaker trabeculae to stronger compact muscle. Using developmental series covering the embryonic and foetal periods of human, mouse and chicken, we show ventricular morphol...

Vitamin D deficiency, which is highly prevalent in the general population, exerts similar deleterious effects on skeletal muscles to those induced by cigarette smoking. We examined whether cigarette smoke (CS) exposure and/or vitamin D deficiency impairs the skeletal muscle hypertrophic response to overload. Male C57Bl/6JolaH mice on a normal or vi...

Mouse models have contributed significantly to understanding genetic and physiological factors involved in healthy cardiac function, how perturbations result in pathology, and how myocardial diseases may be treated. Cardiovascular magnetic resonance imaging (CMR) has become an indispensable tool for a comprehensive in vivo assessment of cardiac ana...

Atherosclerosis is a chronic inflammatory cardiovascular disease, which results from lipid accumulation in the blood vessel wall, forming a plaque, and ultimately restricting blood flow. The immune system plays a vital role in progression to plaque rupture. While recent evidence clearly indicates the anti-inflammatory function of regular exercise,...

Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosop...

Skeletal muscle fibrosis and regeneration are modulated by transforming growth factor β (TGF-β) superfamily. Amongst them, TGF-β1 is a highly potent pro-fibrotic factor, while TGF-β3 has been implicated to reduce scar formation and collagen production in skin and vocal mucosa. However, little is known about the individual and combined short- and lo...

Metabolic reprogramming and mitochondrial dysfunction are central elements in a broad variety of physiological and pathological processes. While cell culture established itself as a versatile technique for the elaboration of physiology and disease, studying metabolism using standard cell culture protocols is profoundly interfered by the Crabtree ef...

The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically releva...

Spatiotemporally regulated targeted gene manipulation is a common way to study the effect of gene variants on phenotypic traits, but the Cre/loxP and Tet-On/Tet-Off systems can affect whole-organism physiology and function due to off-target effects. We highlight some of these adverse effects, including whole-body endocrinology and disturbances in t...

Low skeletal muscle mass is highly prevalent in older cancer patients and affects 5% to 89% depending on the type and stage of cancer. Low skeletal muscle mass is associated with poor clinical outcomes such as postoperative complications, chemotherapy toxicity and mortality in older cancer patients. Little is known about the mediating pathophysiolo...

Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyoc...

Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid oxidation. Mitochondrial dysfunction has often been...

INTRODUCTION The severity of microgravity-induced muscle weakness increases with the duration of spaceflight and is a major concern for long-term missions. While muscle wasting and loss of functional innervation are thought to contribute to losses in muscle force, potential microgravity-induced changes in power production (force–velocity relationsh...

Introduction: Apart from its adverse effects on the respiratory system, cigarette smoking also induces skeletal muscle atrophy and dysfunction. Whether short-term smoking cessation can restore muscle mass and function is unknown. We therefore studied the impact of 1- and 2-weeks smoking cessation on skeletal muscles in a mouse model. Methods: Ma...

Background: A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise-induced rhabdomyolysis in patients with fatty acid oxidation (FAO) disorders. We hypothesized that ingestion of a ketone ester (KE) drink prior to exercise could serve as an alternative oxidative substrate supply to...

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF pr...

Aim: Calcium ions play a pivotal role in matching energy supply and demand in cardiac muscle. Mitochondrial calcium concentration is lower in animal models of heart failure with reduced ejection fraction, but limited information is available about mitochondrial calcium handling in heart failure with preserved ejection fraction (HFpEF). Methods:...

Purpose ¹⁹F‐MRI is gaining widespread interest for cell tracking and quantification of immune and inflammatory cells in vivo. Different fluorinated compounds can be discriminated based on their characteristic MR spectra, allowing in vivo imaging of multiple ¹⁹F compounds simultaneously, so‐called multicolor ¹⁹F‐MRI. We introduce a method for multic...

Mitochondrial respiratory states and rates MitoEAGLE Task Group

Atherosclerosis is a prevalent disease affecting a large portion of the population at one point in their lives. There is an unmet need for noninvasive diagnostics to identify and characterize at-risk plaque phenotypes noninvasively and in vivo, to improve the stratification of patients with cardiovascular disease, and for treatment evaluation. Magn...

As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unif...

As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unif...

Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macroph...

As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unif...

Water is indispensable for life. It is the medium in the cell required for biochemical reactions, a main source of evaporative cooling and a solute for waste products in our urine. Water is also the main component of blood that is crucial for the transport of oxygen, hormones and substrates to, and removal of heat and metabolites from, body cells....

The ability to efficiently adapt metabolism by substrate sensing, trafficking, storage and utilization, dependent on availability and requirement is known as metabolic flexibility. In this review, we discuss the breadth and depth of metabolic flexibility and its impact on health and disease. Metabolic flexibility is essential to maintain energy hom...

Mitochondrial fatty acid oxidation is an essential pathway for energy production, especially during prolonged fasting and sub-maximal exercise. Long-chain fatty acids are the most abundant fatty acids in the human diet and in body stores, and more than 15 enzymes are involved in long-chain fatty acid oxidation. Pathogenic mutations in genes encodin...

The rate of oxidative phosphorylation depends on the contractile activity of the heart. Cardiac mitochondrial oxidative phosphorylation is determined by free ADP concentration, mitochondrial Ca2+ accumulation, mitochondrial enzyme activities and Krebs cycle intermediates. The purpose of the present study was to examine the factors that limit oxidat...