A5060754176- Muscle metabolism and nutrition
- Cardiovascular Function and Risk Factors
- Cardiac Ischemia and Reperfusion
- Advanced MRI Techniques and Applications
- Adipose Tissue and Metabolism
- Metabolism and Genetic Disorders
- Diet and metabolism studies
- Heart Failure Treatment and Management
- Cardiomyopathy and Myosin Studies
- Signaling Pathways in Disease
- Animal testing and alternatives
- Cardiovascular Effects of Exercise
- Glycogen Storage Diseases and Myoclonus
- Cardiac Arrest and Resuscitation
- Fuel Cells and Related Materials
- Cardiac Imaging and Diagnostics
- Metabolomics and Mass Spectrometry Studies
- Cellular Mechanics and Interactions
- Nitric Oxide and Endothelin Effects
- Cardiac Fibrosis and Remodeling
- Immune cells in cancer
- Cancer-related Molecular Pathways
- Wnt/β-catenin signaling in development and cancer
- Hormonal Regulation and Hypertension
- Veterinary Pharmacology and Anesthesia
British Heart Foundation
2014-2024
University of Oxford
2014-2024
Centre for Human Genetics
2014-2022
Ludwig-Maximilians-Universität München
2017
Universität Hamburg
2017
University Medical Center Hamburg-Eppendorf
2017
John Radcliffe Hospital
2015
Dystrophic Epidermolysis Bullosa Research Association of America
2015
Monocytes play critical roles in tissue injury and repair following acute myocardial infarction (AMI). Specifically targeting inflammatory monocytes experimental models leads to reduced infarct size improved healing. However, data from humans are sparse, it remains unclear whether an equally important role humans. The aim of this study was investigate the monocyte response AMI is conserved between mice interrogate patterns gene expression identify regulated functions. Thirty patients (AMI)...
Mitochondrial creatine kinase (MtCK) couples ATP production via oxidative phosphorylation to phosphocreatine in the cytosol, which acts as a mobile energy store available for regeneration of at times high demand. We hypothesized that elevating MtCK would be beneficial ischaemia-reperfusion (I/R) injury.Mice were created over-expressing sarcomeric gene with αMHC promoter Rosa26 locus (MtCK-OE) and compared wild-type (WT) littermates. activity was 27% higher than WT, no change other CK...
New Findings What is the central question of this study? There an ethical imperative to optimize analgesia protocols for laboratory animals, but impeded by our inability recognize pain reliably. We examined whether Mouse Grimace Scale (MGS) provides benefits over a standard welfare scoring system identifying low level in frequently used murine surgical model myocardial infarction. main finding and its importance? Low‐level pain, responsive analgesia, was detected MGS not methods. In model,...
Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) kidney catalyses both first step biosynthesis as well homoarginine (HA) synthesis. AGAT-/- mice fed a creatine-free diet have whole body creatine-deficiency. We hypothesized that would develop cardiac dysfunction and rescue by dietary imply causality.Withdrawal of provided...
Abstract Mitochondrial creatine kinase (Mt-CK) is a major determinant of cardiac energetic status and down-regulated in chronic heart failure, which may contribute to disease progression. We hypothesised that cardiomyocyte-specific overexpression Mt-CK would mitigate against these changes thereby preserve function. Male overexpressing mice (OE) WT littermates were subjected transverse aortic constriction (TAC) or sham surgery assessed by echocardiography at 0, 3 6 weeks alongside final LV...
Inhibition of malonyl-coenzyme A decarboxylase (MCD) shifts metabolism from fatty acid towards glucose oxidation, which has therapeutic potential for obesity and myocardial ischemic injury. However, ~40% patients with MCD deficiency are diagnosed cardiomyopathy during infancy.To clarify the link between cardiac dysfunction in early life to determine contributing systemic metabolic perturbations.MCD knockout mice ((-/-)) exhibited non-Mendelian genotype ratios (31% fewer MCD(-/-)) deaths...
Mice over-expressing the creatine transporter have elevated myocardial levels [Cr] and are protected against ischaemia/reperfusion injury via improved energy reserve. However, mice with very high develop cardiac hypertrophy dysfunction. To investigate these contrasting effects, we applied a non-biased hypothesis-generating approach to quantify global protein metabolite changes in LV of stratified for levels: wildtype, moderately elevated, (65–85; 100–135; 160–250 nmol/mg protein,...
Background Multiple studies suggest creatine mediates anti-oxidant activity in addition to its established role cellular energy metabolism. The functional significance for the heart has yet be established, but antioxidant could contribute cardioprotective effect of ischaemia/reperfusion injury. Objectives To determine whether intracellular levels influence responses acute reactive oxygen species (ROS) exposure intact beating heart. We hypothesised that mice with elevated due over-expression...
Aim: Guanidinoacetate N-methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischaemic heart failure. However, we hypothesised long-term consequences of and/or accumulation precursor guanidinoacetate (GA). Methods: Cardiac function metabolic profile were studied >1 year. Results: In vivo LV catheterisation revealed lower rate developed...
Aims Ischaemic heart disease is most prevalent in the ageing population and often exists with other comorbidities; however majority of laboratory research uses young, healthy animal models. Several recent workshops focus meetings have highlighted importance using clinically relevant models to help aid translation realistic patient populations. We previously shown that mice over-expressing creatine transporter (CrT-OE) elevated intracellular levels are protected against ischaemia-reperfusion...
Sarcomere assembly is a highly orchestrated and dynamic process which adapts, during perinatal development, to accommodate growth of the heart. Sarcomeric components, including titin, undergo an isoform transition adjust ventricular filling. Many sarcomeric genes have been implicated in congenital cardiomyopathies, such that understanding developmental sarcomere transitions will inform aetiology treatment. We sought determine whether Thymosin β4 (Tβ4), peptide regulates availability actin...
Aims Adenylate kinase 1 (AK1) catalyses the reaction 2ADP ↔ ATP + AMP, extracting extra energy under metabolic stress and promoting energetic homeostasis. We hypothesised that increased AK1 activity would have negligible effects at rest, but protect against ischaemia/reperfusion (I/R) injury. Methods Results Cardiac-specific overexpressing mice (AK1-OE) had 31% higher ( P = 0.009), with unchanged total creatine citrate synthase activities. Male AK1-OE exhibited mild in vivo dysfunction...
Organisms obtain creatine from their diet or by de novo synthesis via AGAT (L-arginine:glycine amidinotransferase) and GAMT (Guanidinoacetate N-methyltrasferase) in kidney liver, respectively. also synthesizes homoarginine (hArg), low levels of which predict poor outcomes human cardiovascular disease, while supplementation maintains contractility murine heart failure. However, the expression pattern has not been systematically studied mouse tissues nothing is known about potential feedback...
Low levels of homoarginine and creatine are associated with heart failure severity in humans, but it is unclear to what extent they contribute pathophysiology. Both synthesized via L-arginine:glycine amidinotransferase (AGAT), such that AGAT-/- mice have a combined deficiency. We hypothesized this would be detrimental the setting chronic failure.Study 1: deficiency-female wild-type were given creatine-supplemented diet so both had normal myocardial levels, only low plasma homoarginine....
Phosphorus cardiovascular magnetic resonance spectroscopy (31P-CMRS) has emerged as an important tool for the preclinical assessment of myocardial energetics in vivo. However, high rate and diminutive size mouse heart is a challenge, resulting low resolution poor signal-to-noise. Here we describe refined high-resolution 31P-CMRS technique apply it to novel double transgenic (dTg) with elevated creatine kinase (CK) activity. We hypothesised synergistic effect augment energetic status,...
Introduction: Homoarginine (HA) is an emerging biomarker with low levels associated increased risk of stroke, myocardial infarction and heart failure (HF) in epidemiological studies. Recently, we identified HA as independent predictor mortality patients HF. We therefore hypothesized that supplementation might be beneficial a murine model chronic failure. Methods: C57BL/6J mice were treated 14 mg/L drinking water for 4 weeks prior to coronary artery occlusion induce infarction. Infarct size...