676 results on '"John Vissing"'
Search Results
2. Pulmonary vascular adaptations to hypoxia in elite breath-hold divers
- Author
-
Thomas Kjeld, Anders Brenøe Isbrand, Henrik Christian Arendrup, Jens Højberg, Jacob Bejder, Thomas O. Krag, John Vissing, Lars Poulsen Tolbod, Johannes Hendrik Harms, Lars Christian Gormsen, Dan Fuglø, and Egon Godthaab Hansen
- Subjects
cardiac MR (CMR) ,cardiac PET/CT ,echocardiagraphy ,freediving ,cardiac output ,Physiology ,QP1-981 - Abstract
IntroductionElite breath-hold divers (BHD) possess several oxygen conserving adaptations to endure long dives similar to diving mammals. During dives, Bottlenose Dolphins may increase the alveolar ventilation (VA) to perfusion (Q) ratio to increase alveolar oxygen delivery. We hypothesized that BHD possess similar adaptive mechanisms during apnea.Methods and resultsPulmonary blood volume (PBV) was determined by echocardiography, 15O-H2O PET/CT, and cardiac MRi, (n = 6) during and after maximum apneas. Pulmonary function was determined by body box spirometry and compared to matched controls. After 2 min of apnea, the PBV determined by echocardiography and 15O-H2O-PET/CT decreased by 26% and 41%, respectively. After 4 min of apnea, the PBV assessed by echocardiography and cardiac MRi decreased by 48% and 67%, respectively (n = 6). Fractional saturation (F)O2Hb determined by arterial blood-gas-analyses collected after warm-up and a 5-minute pool-apnea (n = 9) decreased by 43%. Compared to matched controls (n = 8), spirometry revealed a higher total and alveolar-lung-capacity in BHD (n = 9), but a lower diffusion-constant.ConclusionOur results contrast with previous studies, that demonstrated similar lung gas transfer in BHD and matched controls. We conclude that elite BHD 1) have a lower diffusion constant than matched controls, and 2) gradually decrease PBV during apnea and in turn increase VA/Q to increase alveolar oxygen delivery during maximum apnea. We suggest that BHD possess pulmonary adaptations similar to diving mammals to tolerate decreasing tissue oxygenation.New and noteworthyThis manuscript addresses novel knowledge on tolerance to hypoxia during diving, which is shared by elite breath-hold divers and adult diving mammals: Our study indicates that elite breath-hold divers gradually decrease pulmonary blood volume and in turn increase VA/Q, to increase alveolar oxygen delivery during maximum apnea to tolerate decreasing oxygen levels similar to the Bottlenose Dolphin.
- Published
- 2024
- Full Text
- View/download PDF
3. Hemoglobin concentration and blood shift during dry static apnea in elite breath hold divers
- Author
-
Thomas Kjeld, Thomas O. Krag, Anders Brenøe, Ann Merete Møller, Henrik Christian Arendrup, Jens Højberg, Dan Fuglø, Søren Hancke, Lars Poulsen Tolbod, Lars Christian Gormsen, John Vissing, and Egon Godthaab Hansen
- Subjects
cardiac PET/CT ,cardiac MR (CMR) ,spleen ultrasound examination ,dual x-ray absorptiometry (DXA) ,Bohr effect ,free diving ,Physiology ,QP1-981 - Abstract
IntroductionElite breath-hold divers (BHD) enduring apneas of more than 5 min are characterized by tolerance to arterial blood oxygen levels of 4.3 kPa and low oxygen-consumption in their hearts and skeletal muscles, similar to adult seals. Adult seals possess an adaptive higher hemoglobin-concentration and Bohr effect than pups, and when sedated, adult seals demonstrate a blood shift from the spleen towards the brain, lungs, and heart during apnea. We hypothesized these observations to be similar in human BHD. Therefore, we measured hemoglobin- and 2,3-biphosphoglycerate-concentrations in BHD (n = 11) and matched controls (n = 11) at rest, while myocardial mass, spleen and lower extremity volumes were assessed at rest and during apnea in BHD.Methods and resultsAfter 4 min of apnea, left ventricular myocardial mass (LVMM) determined by 15O-H2O-PET/CT (n = 6) and cardiac MRI (n = 6), was unaltered compared to rest. During maximum apnea (∼6 min), lower extremity volume assessed by DXA-scan revealed a ∼268 mL decrease, and spleen volume, assessed by ultrasonography, decreased ∼102 mL. Compared to age, BMI and VO2max matched controls (n = 11), BHD had similar spleen sizes and 2,3- biphosphoglycerate-concentrations, but higher total hemoglobin-concentrations.ConclusionOur results indicate: 1) Apnea training in BHD may increase hemoglobin concentration as an oxygen conserving adaptation similar to adult diving mammals. 2) The blood shift during dry apnea in BHD is 162% more from the lower extremities than from the spleen. 3) In contrast to the previous theory of the blood shift demonstrated in sedated adult seals, blood shift is not towards the heart during dry apnea in humans.
- Published
- 2024
- Full Text
- View/download PDF
4. Data from the European registry for patients with McArdle disease (EUROMAC): functional status and social participation
- Author
-
Walaa Karazi, Renata S. Scalco, Mads G. Stemmerik, Nicoline Løkken, Alejandro Lucia, Alfredo Santalla, Andrea Martinuzzi, Marinela Vavla, Gianluigi Reni, Antonio Toscano, Olimpia Musumeci, Carlyn V. Kouwenberg, Pascal Laforêt, Beatriz San Millán, Irene Vieitez, Gabriele Siciliano, Enrico Kühnle, Rebecca Trost, Sabrina Sacconi, Hacer Durmus, Biruta Kierdaszuk, Andrew Wakelin, Antoni L. Andreu, Tomàs Pinós, Ramon Marti, Ros Quinlivan, John Vissing, Nicol C. Voermans, and EUROMAC Consortium
- Subjects
McArdle disease ,Glycogen storage disease V ,Rare diseases ,International registry ,Health care ,Medicine - Abstract
Abstract Background The European registry for individuals with GSD5 and other muscle glycogenosis (EUROMAC) was launched to register rare muscle glycogenosis in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases. A network of twenty collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. Methods Following the initial report on demographics, neuromuscular features and comorbidity (2020), we here present the data on social participation, previous and current treatments (medication, supplements, diet and rehabilitation) and limitations. Furthermore, the following questionnaires were used: Fatigue severity scale (FSS), WHO Disability Assessment Scale (DAS 2.0), health related quality of life (SF36) and International Physical Activity Questionnaire (IPAQ). Results Of 282 participants with confirmed diagnoses of muscle glycogenosis, 269 had GSD5. Of them 196 (73%) completed all questionnaires; for the others, the data were incomplete. The majority, 180 (67%) were currently working. Previous medical treatments included pain medication (23%) and rehabilitation treatment (60%). The carbohydrate-rich diet was reported to be beneficial for 68%, the low sucrose diet for 76% and the ketogenic diet for 88%. Almost all participants (93%) reported difficulties climbing stairs. The median FSS score was 5.22, indicating severe fatigue. The data from the WHODAS and IPAQ was not of sufficient quality to be interpreted. Conclusions The EUROMAC registry have provided insight into the functional and social status of participants with GSD5: most participants are socially active despite limitations in physical and daily life activities. Regular physical activity and different dietary approaches may alleviate fatigue and pain.
- Published
- 2023
- Full Text
- View/download PDF
5. Muscle fat replacement and contractility in patients with skeletal muscle sodium channel disorders
- Author
-
Jonas Jalili Pedersen, Mads Godtfeldt Stemmerik, Laura Nørager Jacobsen, Sofie Vinther Skriver, Gustav Rhode Wilms, Morten Duno, and John Vissing
- Subjects
Medicine ,Science - Abstract
Abstract Skeletal muscle sodium channel disorders give rise to episodic symptoms such as myotonia and/or periodic paralysis. Chronic symptoms with permanent weakness are not considered characteristic of the phenotypes. Muscle fat replacement represents irreversible damage that inevitably will impact on muscle strength. This study investigates muscle fat replacement and contractility in patients with pathogenic SCN4A variants compared to healthy controls. T1-weighted and 2-point Dixon MRI of the legs were conducted to assess fat replacement. Stationary dynamometry was used to assess muscle strength. Contractility was determined by maximal muscle contraction divided by cross-sectional muscle area. The average cross-sectional intramuscular fat fraction was greater in patients compared with controls by 2.5% in the calves (95% CI 0.74–4.29%, p = 0.007) and by 2.0% in the thighs (95% CI 0.75–3.2%, p = 0.003). Muscle contractility was less in patients vs. controls by 14–27% (p
- Published
- 2023
- Full Text
- View/download PDF
6. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases
- Author
-
Gabriel Sturm, Kalpita R. Karan, Anna S. Monzel, Balaji Santhanam, Tanja Taivassalo, Céline Bris, Sarah A. Ware, Marissa Cross, Atif Towheed, Albert Higgins-Chen, Meagan J. McManus, Andres Cardenas, Jue Lin, Elissa S. Epel, Shamima Rahman, John Vissing, Bruno Grassi, Morgan Levine, Steve Horvath, Ronald G. Haller, Guy Lenaers, Douglas C. Wallace, Marie-Pierre St-Onge, Saeed Tavazoie, Vincent Procaccio, Brett A. Kaufman, Erin L. Seifert, Michio Hirano, and Martin Picard
- Subjects
Biology (General) ,QH301-705.5 - Abstract
A meta-analysis of 17 cohorts of mitochondrial disease patients reveals that OxPhos defects are associated with signs of hypermetabolism. Experiments in patient-derived fibroblast show that mitochondrial OxPhos defects trigger hypermetabolism in a cell-autonomous manner and this is linked to accelerated telomere shortening and epigenetic aging.
- Published
- 2023
- Full Text
- View/download PDF
7. NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy
- Author
-
Natasha Ranu, Jenni Laitila, Hannah F. Dugdale, Jennifer Mariano, Justin S. Kolb, Carina Wallgren-Pettersson, Nanna Witting, John Vissing, Juan Jesus Vilchez, Chiara Fiorillo, Edmar Zanoteli, Mari Auranen, Manu Jokela, Giorgio Tasca, Kristl G. Claeys, Nicol C. Voermans, Johanna Palmio, Sanna Huovinen, Maurizio Moggio, Thomas Nyegaard Beck, Aikaterini Kontrogianni-Konstantopoulos, Henk Granzier, and Julien Ochala
- Subjects
Skeletal muscle ,Nemaline myopathy ,Nebulin ,Myosin ,Metabolism ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients’ muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin‐deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin‐deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.
- Published
- 2022
- Full Text
- View/download PDF
8. β‐Galactosidase deficiency in the GLB1 spectrum of lysosomal storage disease can present with severe muscle weakness and atrophy
- Author
-
Jonas Jalili Pedersen, Morten Duno, Flemming Wibrand, Christian Hammer, Thomas Krag, and John Vissing
- Subjects
fat replacement ,GLB1‐related disorders ,metabolic neuromuscular disorder ,Morquio B ,muscle wasting ,myopathy ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Genetics ,QH426-470 - Abstract
Abstract Deficiency of the enzyme β‐galactosidase due to variants in the GLB1‐gene is associated with metabolic disorders: Morquio B and GM1‐gangliosidosis. Here, we report a case compound heterozygous for variants in the GLB1‐gene and a severe muscular phenotype. Full body T1‐w MRI was conducted for muscular involvement. Biopsy was stained with hematoxylin and eosin for histopathological evaluation. EDTA blood‐sample was subjected to whole exome sequencing. Metabolic analysis included residual enzyme activity and evaluation urinary substrate secretion. Additionally, electroneurography, echocardiography, forced volume capacity and biochemistry were evaluated. Examination showed severe proximal weakness (MRC: hip flexion 2, hip extension 2, and shoulder rotation 2), Gower's sign, no extrapyramidal symptoms and normal creatine kinase levels. MRI showed severe muscle wasting of the thigh and shoulder girdle. Muscle biopsy showed mild myopathic changes. β‐galactosidase activity was reduced to 28%–34%. Urinary glycosaminoglycan was elevated by 5.9–8.6 mg/mmol (ref.:0–5.1 mg/mmol). Electrophoresis indicated excess keratan sulfate. Exome sequencing revealed two missense variants in the GLB1 gene. Clinical features, genetic testing and laboratory findings indicate a case of β‐galactosidase‐deficiency with a muscular phenotype.
- Published
- 2022
- Full Text
- View/download PDF
9. Energy metabolism during exercise in patients with β‐enolase deficiency (GSDXIII)
- Author
-
Astrid Emilie Buch, Olimpia Musumeci, Ralph Wigley, Mads Peter Godtfeldt Stemmerik, Anne‐Sofie Vibæk Eisum, Karen Lindhardt Madsen, Nicolai Preisler, David Hilton‐Jones, Ros Quinlivan, Antonio Toscano, and John Vissing
- Subjects
β‐enolase deficiency ,exercise intolerance ,exercise metabolism ,GSDXIII ,maximal exercise capacity ,metabolic myopathy ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Genetics ,QH426-470 - Abstract
Abstract Aim To investigate the in vivo skeletal muscle metabolism in patients with β‐enolase deficiency (GSDXIII) during exercise, and the effect of glucose infusion. Methods Three patients with GSDXIII and 10 healthy controls performed a nonischemic handgrip test as well as an incremental cycle ergometer test measuring maximal oxidative consumption (VO2max) and a 1‐hour submaximal cycle test at an intensity of 65% to 75% of VO2max. The patients repeated the submaximal exercise after 2 days, where they received a 10% iv‐glucose supplementation. Results Patients had lower VO2max than healthy controls, and two of three patients had to stop prematurely during the intended 1‐hour submaximal exercise test. During nonischemic forearm test, all patients were able to produce lactate in normal amounts. Glucose infusion had no effect on patients' exercise capacity. Conclusions Patients with GSDXIII experience exercise intolerance and episodes of myoglobinuria, even to the point of needing renal dialysis, but still retain an almost normal anaerobic metabolic response to submaximal intensity exercise. In accordance with this, glucose supplementation did not improve exercise capacity. The findings show that GSDXIII, although causing episodic rhabdomyolysis, is one of the mildest metabolic myopathies affecting glycolysis.
- Published
- 2021
- Full Text
- View/download PDF
10. Autophagy is affected in patients with hypokalemic periodic paralysis: an involvement in vacuolar myopathy?
- Author
-
Thomas O. Krag, Sonja Holm-Yildiz, Nanna Witting, and John Vissing
- Subjects
Hypokalemic periodic paralysis ,CACNA1S ,Vacuoles ,Autophagy ,TFEB ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Hypokalemic periodic paralysis is an autosomal dominant, rare disorder caused by variants in the genes for voltage-gated calcium channel CaV1.1 (CACNA1S) and NaV1.4 (SCN4A). Patients with hypokalemic periodic paralysis may suffer from periodic paralysis alone, periodic paralysis co-existing with permanent weakness or permanent weakness alone. Hypokalemic periodic paralysis has been known to be associated with vacuolar myopathy for decades, and that vacuoles are a universal feature regardless of phenotype. Hence, we wanted to investigate the nature and cause of the vacuoles. Fourteen patients with the p.R528H variation in the CACNA1S gene was included in the study. Histology, immunohistochemistry and transmission electron microscopy was used to assess general histopathology, ultrastructure and pattern of expression of proteins related to muscle fibres and autophagy. Western blotting and real-time PCR was used to determine the expression levels of proteins and mRNA of the proteins investigated in immunohistochemistry. Histology and transmission electron microscopy revealed heterogenous vacuoles containing glycogen, fibrils and autophagosomes. Immunohistochemistry demonstrated autophagosomes and endosomes arrested at the pre-lysosome fusion stage. Expression analysis showed a significant decrease in levels of proteins an mRNA involved in autophagy in patients, suggesting a systemic effect. However, activation level of the master regulator of autophagy gene transcription, TFEB, did not differ between patients and controls, suggesting competing control over autophagy gene transcription by nutritional status and calcium concentration, both controlling TFEB activity. The findings suggest that patients with hypokalemic periodic paralysis have disrupted autophagic processing that contribute to the vacuoles seen in these patients.
- Published
- 2021
- Full Text
- View/download PDF
11. Patient-Reported Experiences with a Low-Carbohydrate Ketogenic Diet: An International Survey in Patients with McArdle Disease
- Author
-
Nicoline Løkken, Nicol C. Voermans, Linda K. Andersen, Walaa Karazi, Stacey L. Reason, Heidi Zweers, Gustav Wilms, Alfredo Santalla, Edward Susanibar, Alejandro Lucia, and John Vissing
- Subjects
McArdle disease ,ketogenic diet ,low carbohydrate ketogenic diet ,glycogen storage disease type V ,survey ,patient-reported experiences ,Nutrition. Foods and food supply ,TX341-641 - Abstract
The low-carbohydrate ketogenic diet (LCKD) has attracted increased attention in recent years as a potential treatment option for individuals with McArdle disease (glycogen storage disease type V), and despite the absence of strong scientific evidence of the LCKD’s benefits, increased numbers of individuals with McArdle disease have tried a LCKD. The objective of this study was to collect patient-reported experiences with a LCKD. We aimed to estimate the immediate prevalence of individuals that had tried a LCKD in an international McArdle disease cohort, and we aimed to report on the patient-reported experiences with the diet, both positive and negative. A total of 183 responses were collected from individuals with McArdle disease from 18 countries. We found that one-third of the cohort had tried a LCKD, and almost 90% experienced some degree of positive effect, with the most prominent effects on McArdle disease-related core symptoms (e.g., activity intolerance, muscle pain, and muscle fatigue). Adverse effects were rare and generally rated as mild to moderate. These patient-reported findings underline the need for randomized clinical trials to decisively determine if a LCKD is a suitable nutritional strategy for patients with McArdle disease. The results from this study can prompt and contribute to the design of such a clinical trial.
- Published
- 2023
- Full Text
- View/download PDF
12. Creation and implementation of a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC registry)
- Author
-
Tomàs Pinós, Antoni L. Andreu, Claudio Bruno, Georgios M. Hadjigeorgiou, Ronald G. Haller, Pascal Laforêt, Alejandro Lucía, Miguel A. Martín, Andrea Martinuzzi, Carmen Navarro, Piraye Oflazer, Jean Pouget, Ros Quinlivan, Sabrina Sacconi, Renata S. Scalco, Antonio Toscano, John Vissing, Matthias Vorgerd, Andrew Wakelin, Ramon Martí, and EUROMAC Consortium
- Subjects
Myopathy ,Rare diseases ,International registry ,McArdle disease ,Metabolic diseases ,Glycogen storage disease ,Medicine - Abstract
Abstract Background International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders. Results Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients. Conclusion EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level.
- Published
- 2020
- Full Text
- View/download PDF
13. Responsiveness of outcome measures in myotonic dystrophy type 1
- Author
-
Kirsten L. Knak, Aisha M. Sheikh, Nanna Witting, and John Vissing
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective As myotonic dystrophy type 1(DM1) evolves slowly and interventional trials often have a short duration, responsive outcomes in DM1 are needed. The objective of this study was to determine the responsiveness of muscle strength, balance, and functional mobility measurements after a 1‐year follow‐up period in individuals with DM1. Methods Sixty‐three adults with noncongenital DM1 completed the following assessments at baseline and at 1‐year follow‐up: Handheld dynamometry (lower limbs), stationary dynamometry (lower limbs), step test, timed‐up‐and‐go test (TUG), modified clinical test of sensory integration and balance (mCTSIB), feet‐together stance, tandem stance, one‐leg stance, 10‐meter walk test, and sit‐to‐stand test. Results Change was captured by stationary dynamometry (proximal flexor and extensor muscles), handheld dynamometry (proximal flexor and distal extensor muscles), TUG, and mCTSIB (P ≤ 0.04). Ceiling or floor effects were shown for most static balance tests. Interpretation Overall, adequate responsiveness was shown for both muscle strength dynamometers, TUG and mCTSIB. These outcomes are therefore likely candidate endpoints for clinical trials lasting 1 year. Most static balance tests are not responsive and not recommended in a heterogeneous DM1 population.
- Published
- 2020
- Full Text
- View/download PDF
14. Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9
- Author
-
Lindsay B. Murphy, Olivia Schreiber‐Katz, Karen Rafferty, Agata Robertson, Ana Topf, Tracey A. Willis, Marcel Heidemann, Simone Thiele, Laurence Bindoff, Jean‐Pierre Laurent, Hanns Lochmüller, Katherine Mathews, Claudia Mitchell, John Herbert Stevenson, John Vissing, Lacey Woods, Maggie C. Walter, and Volker Straub
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective The Global FKRP Registry is a database for individuals with conditions caused by mutations in the Fukutin‐Related Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, Muscle–Eye–Brain Disease and Walker–Warburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRP‐related conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities. Methods Registration is patient‐initiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain. Results Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C > A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C > A compared with individuals heterozygous for c.826C > A. This divergence was replicated in ages of loss of running ability, wheelchair‐dependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C > A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129). Interpretation The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trial‐ready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies.
- Published
- 2020
- Full Text
- View/download PDF
15. Impaired lipolysis in propionic acidemia: A new metabolic myopathy?
- Author
-
Jesper H. Storgaard, Karen L. Madsen, Nicoline Løkken, John Vissing, Gerrit vanHall, Allan M. Lund, and Mette C. Ørngreen
- Subjects
carbohydrate metabolism ,exercise metabolism ,fat metabolism ,metabolic myopathy ,organic aciduria ,propionic acidemia ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Genetics ,QH426-470 - Abstract
Abstract The objective of this study was to investigate the fat and carbohydrate metabolism in a patient with propionic acidemia (PA) during exercise by means of indirect calorimetry and stable isotope technique. A 34‐year‐old patient with PA performed a 30‐minute submaximal cycle ergometer test. Data were compared to results from six gender‐ and age‐matched healthy controls. Main findings are that the patient with PA had impaired lipolysis, blunted fatty acid oxidation, compensatory increase in carbohydrate utilization, and low work capacity. Our findings indicate that PA should be added to the list of metabolic myopathies.
- Published
- 2020
- Full Text
- View/download PDF
16. No effect of triheptanoin on exercise performance in McArdle disease
- Author
-
Karen L. Madsen, Pascal Laforêt, Astrid E. Buch, Mads G. Stemmerik, Chris Ottolenghi, Stéphane N. Hatem, Daniel T. Raaschou‐Pedersen, Nanna S. Poulsen, Maria Atencio, Marie‐Pierre Luton, Alexandre Ceccaldi, Ronald G. Haller, Ros Quinlivan, Fanny Mochel, and John Vissing
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective To study if treatment with triheptanoin, a 7‐carbon triglyceride, improves exercise tolerance in patients with McArdle disease. McArdle patients have a complete block in glycogenolysis and glycogen‐dependent expansion of tricarboxylic acid cycle (TCA), which may restrict fat oxidation. We hypothesized that triheptanoin metabolism generates substrates for the TCA, which potentially boosts fat oxidation and improves exercise tolerance in McArdle disease. Methods Double‐blind, placebo‐controlled, crossover study in patients with McArdle disease completing two treatment periods of 14 days each with a triheptanoin or placebo diet (1 g/kg/day). Primary outcome was change in mean heart rate during 20 min submaximal exercise on a cycle ergometer. Secondary outcomes were change in peak workload and oxygen uptake along with changes in blood metabolites and respiratory quotients. Results Nineteen of 22 patients completed the trial. Malate levels rose on triheptanoin treatment versus placebo (8.0 ± SD2.3 vs. 5.5 ± SD1.8 µmol/L, P
- Published
- 2019
- Full Text
- View/download PDF
17. Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment
- Author
-
Pascal Laforêt, Michio Inoue, Evelyne Goillot, Claire Lefeuvre, Umut Cagin, Nathalie Streichenberger, Sarah Leonard-Louis, Guy Brochier, Angeline Madelaine, Clemence Labasse, Carola Hedberg-Oldfors, Thomas Krag, Louisa Jauze, Julien Fabregue, Philippe Labrune, Jose Milisenda, Aleksandra Nadaj-Pakleza, Sabrina Sacconi, Federico Mingozzi, Giuseppe Ronzitti, François Petit, Benedikt Schoser, Anders Oldfors, John Vissing, Norma B. Romero, Ichizo Nishino, and Edoardo Malfatti
- Subjects
Glycogen storage disease III ,Muscle glycogenosis ,Metabolic myopathies ,Myopathology ,Autophagy ,Autophagic impairment ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.
- Published
- 2019
- Full Text
- View/download PDF
18. Extreme Hypoxia Causing Brady-Arrythmias During Apnea in Elite Breath-Hold Divers
- Author
-
Thomas Kjeld, Anders Brenøe Isbrand, Katrine Linnet, Bo Zerahn, Jens Højberg, Egon Godthaab Hansen, Lars Christian Gormsen, Jacob Bejder, Thomas Krag, John Vissing, Hans Erik Bøtker, and Henrik Christian Arendrup
- Subjects
junctional rhythm ,brady-arrythmia ,free-diving ,invasive blood pressure ,hypoxia induced factor-1 (HIF-1) ,atrioventricular block ,Physiology ,QP1-981 - Abstract
Introduction: The cardiac electrical conduction system is very sensitive to hypoglycemia and hypoxia, and the consequence may be brady-arrythmias. Weddell seals endure brady-arrythmias during their dives when desaturating to 3.2 kPa and elite breath-hold-divers (BHD), who share metabolic and cardiovascular adaptions including bradycardia with diving mammals, endure similar desaturation during maximum apnea. We hypothesized that hypoxia causes brady-arrythmias during maximum apnea in elite BHD. Hence, this study aimed to define the arterial blood glucose (Glu), peripheral saturation (SAT), heart rhythm (HR), and mean arterial blood pressure (MAP) of elite BHD during maximum apneas.Methods: HR was monitored with Direct-Current-Pads/ECG-lead-II and MAP and Glu from a radial arterial-catheter in nine BHD performing an immersed and head-down maximal static pool apnea after three warm-up apneas. SAT was monitored with a sensor on the neck of the subjects. On a separate day, a 12-lead-ECG-monitored maximum static apnea was repeated dry (n = 6).Results: During pool apnea of maximum duration (385 ± 70 s), SAT decreased from 99.6 ± 0.5 to 58.5 ± 5.5% (∼PaO2 4.8 ± 1.5 kPa, P < 0.001), while Glu increased from 5.8 ± 0.2 to 6.2 ± 0.2 mmol/l (P = 0.009). MAP increased from 103 ± 4 to 155 ± 6 mm Hg (P < 0.005). HR decreased to 46 ± 10 from 86 ± 14 beats/minute (P < 0.001). HR and MAP were unchanged after 3–4 min of apnea. During dry apnea (378 ± 31 s), HR decreased from 55 ± 4 to 40 ± 3 beats/minute (P = 0.031). Atrioventricular dissociation and junctional rhythm were observed both during pool and dry apneas.Conclusion: Our findings contrast with previous studies concluding that Glu decreases during apnea diving. We conclude during maximum apnea in elite BHD that (1) the diving reflex is maximized after 3–4 min, (2) increasing Glu may indicate lactate metabolism in accordance with our previous results, and (3) extreme hypoxia rather than hypoglycemia causes brady-arrythmias in elite BHD similar to diving mammals.
- Published
- 2021
- Full Text
- View/download PDF
19. Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity
- Author
-
Astrid L. Basse, Marianne Agerholm, Jean Farup, Emilie Dalbram, Joachim Nielsen, Niels Ørtenblad, Ali Altıntaş, Amy M. Ehrlich, Thomas Krag, Santina Bruzzone, Morten Dall, Roldan M. de Guia, Jonas B. Jensen, Andreas B. Møller, Anders Karlsen, Michael Kjær, Romain Barrès, John Vissing, Steen Larsen, Niels Jessen, and Jonas T. Treebak
- Subjects
Cyclophilin D ,Mitochondrial permeability transition pore (mPTP) ,Myopathy ,NAD+ ,Nicotinamide riboside ,Sarcopenia ,Internal medicine ,RC31-1245 - Abstract
Objective: NAD+ is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD+ synthesis, and in skeletal muscle, NAD+ is essential for muscle integrity. However, the underlying molecular mechanisms by which NAD+ synthesis affects muscle health remain poorly understood. Thus, the objective of the current study was to delineate the role of NAMPT-mediated NAD+ biosynthesis in skeletal muscle development and function. Methods: To determine the role of Nampt in muscle development and function, we generated skeletal muscle-specific Nampt KO (SMNKO) mice. We performed a comprehensive phenotypic characterization of the SMNKO mice, including metabolic measurements, histological examinations, and RNA sequencing analyses of skeletal muscle from SMNKO mice and WT littermates. Results: SMNKO mice were smaller, with phenotypic changes in skeletal muscle, including reduced fiber area and increased number of centralized nuclei. The majority of SMNKO mice died prematurely. Transcriptomic analysis identified that the gene encoding the mitochondrial permeability transition pore (mPTP) regulator Cyclophilin D (Ppif) was upregulated in skeletal muscle of SMNKO mice from 2 weeks of age, with associated increased sensitivity of mitochondria to the Ca2+-stimulated mPTP opening. Treatment of SMNKO mice with the Cyclophilin D inhibitor, Cyclosporine A, increased membrane integrity, decreased the number of centralized nuclei, and increased survival. Conclusions: Our study demonstrates that NAMPT is crucial for maintaining cellular Ca2+ homeostasis and skeletal muscle development, which is vital for juvenile survival.
- Published
- 2021
- Full Text
- View/download PDF
20. Quantitative Muscle MRI and Clinical Findings in Women With Pathogenic Dystrophin Gene Variants
- Author
-
Freja Fornander, Tuva Åsatun Solheim, Anne-Sofie Vibæk Eisum, Nanna Scharff Poulsen, Annarita Ghosh Andersen, Julia Rebecka Dahlqvist, Morten Dunø, and John Vissing
- Subjects
dystrophinopathy ,female carriers ,Dixon MRI ,muscle fat infiltration ,dynamometry ,muscle strength ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Objective: To explore fat replacement, muscle strength, and clinical features in women heterozygous for a pathogenic DMD variant, we prospectively examined 53 women, assuming that some of these women—despite of the recessive X-linked inheritance—manifested clinical symptoms.Methods: We performed a cross-sectional observational study using MRI and stationary dynamometry of lower extremities, extracted blood muscle biomarkers, and investigated subjective complaints. Results were compared with 19 healthy women.Results:DMD variant carriers were weaker and had higher fat fractions than controls in all investigated muscle groups (p < 0.02). Fat fractions were 18% in carriers vs. 11% in controls in thighs (p = 0.008), and 15 vs. 11% in calf muscles (p = 0.032). Seventy-two percent had fat fractions deviating from controls by two standard deviations (SDs) in one or more of the 16 investigated muscle groups. On strength testing, 40% of the carriers had results deviating from control muscle strength by two SDs in one or more dynamometry assessments. Forty-three carriers (81%) had either reduced muscle strength (2 SDs from control mean). Thirty of these had subjective symptoms. Blood creatine kinase and myoglobin were elevated in 57% of the carriers.Conclusion: Using quantitative methods, this study shows that both clinically symptomatic and asymptomatic women with pathogenic DMD variants show a high prevalence of muscle affection. Longitudinal studies in female carriers of pathogenic DMD variants are needed to follow the evolution of these changes.
- Published
- 2021
- Full Text
- View/download PDF
21. Cardiac Involvement in Women With Pathogenic Dystrophin Gene Variants
- Author
-
Tuva Å. Solheim, Freja Fornander, Anna A. Raja, Rasmus Møgelvang, Nanna S. Poulsen, Morten Dunø, Henning Bundgaard, and John Vissing
- Subjects
dystrophinopathy ,female carriers ,cardiac MRI ,echocardiography ,cardiac ,cardiac involvement ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Objective: To determine the frequency and extent of cardiac involvement in female carriers of pathogenic variants in DMD, 53 women were examined through an observational, cross-sectional study.Methods: Genetically verified female carriers of pathogenic DMD variants were examined by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement, echocardiography, 24-h Holter monitoring, ECG, and blood concentrations of skeletal and cardiac muscle biomarkers.Results: Fifty-three female carriers of pathogenic DMD variants (mean age 49.6 years, 33 associated with DMD, and 20 with BMD) were included in the study. Sixty-two percent had cardiac dysfunction on echocardiography. On CMR, 49% had myocardial fibrosis, 35% had dilated left ventricles, and 10% had left ventricular hypertrophy. ECGs were abnormal in 72%, and abnormal Holter monitoring was found in 43%. Age did not correlate with myocardial fibrosis or cardiac dysfunction. Myocardial fibrosis was more frequent in carriers of pathogenic variants associated with DMD vs. BMD (61 vs. 28%, p = 0.02).Conclusion: This study shows that cardiac involvement, affecting both structure and function of the heart, is found in over 2/3 of women with a pathogenic DMD variant. The study supports early cardiac screening, including ECG, Holter, and cardiac imaging, in this group of carriers, so that symptoms related to pathogenic variants in DMD can be recognized, and relevant treatment can be initiated. Longitudinal studies are needed to assess morbidity and mortality related to single, pathogenic DMD variants in women.
- Published
- 2021
- Full Text
- View/download PDF
22. Function, structure and quality of striated muscles in the lower extremities in patients with late onset Pompe Disease—an MRI study
- Author
-
Michael Vaeggemose, Rosa Andersen Mencagli, Julie Schjødtz Hansen, Bianca Dräger, Steffen Ringgaard, John Vissing, and Henning Andersen
- Subjects
Late Onset Pompe Disease ,Quantitative magnetic resonance imaging (mri) ,Muscle quality ,Enzyme replacement therapy ,Clinical tests ,Follow-up ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background Pompe Disease (PD) is a rare inherited metabolic myopathy, caused by lysosomal-α-glucosidase (GAA) deficiency, which leads to glycogen accumulation within the lysosomes, resulting in cellular and tissue damage. Due to the emergence of a disease modifying treatment with recombinant GAA there has been a large increase in studies of late onset Pompe Disease (LOPD) during the last decade. Methods The present study evaluates muscle quality in 10 patients with LOPD receiving treatment with enzyme replacement therapy and in 10 age and gender matched healthy controls applying T1-weighted Dixon MR imaging and isokinetic dynamometry. Muscle quality was determined by muscle strength in relation to muscle size (contractile cross-sectional area, CSA) and to muscle quality (fat fraction). A follow-up evaluation of the patients was performed after 8–12 months. Patient evaluations also included: six-minute walking test (6MWT), forced vital capacity, manual muscle testing and SF-36 questionnaire. Results Fat fraction of knee flexors (0.15 vs 0.07, p
- Published
- 2021
- Full Text
- View/download PDF
23. Patients With Becker Muscular Dystrophy Have Severe Paraspinal Muscle Involvement
- Author
-
Aisha M. Sheikh, Karen Rudolf, Josefine de Stricker Borch, Tahmina Khawajazada, Nanna Witting, and John Vissing
- Subjects
paraspinal muscles ,Becker muscular dystrophy ,quantitative muscle MRI ,quantitative trunk strength ,fat fraction ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Introduction: Paraspinal muscles are important for gross motor functions. Impairment of these muscles can lead to poor postural control and ambulation difficulty. Little knowledge exists about the involvement of paraspinal muscles in Becker muscular dystrophy.Objective: In this cross-sectional study, we investigated the involvement of paraspinal muscles with quantitative trunk strength measure and quantitative muscle MRI.Methods and Materials: Eighteen patients with Becker muscular dystrophy underwent trunk, hip, and thigh strength assessment using a Biodex dynamometer and an MRI Dixon scan. Fourteen age- and body mass index-matched healthy men were included for comparison.Results: Muscle fat fraction (FF) of the paraspinal muscles (multifidus and erector spinae) was higher in participants with Becker muscular dystrophy vs. healthy controls at all three examined spinal levels (C6, Th12, and L4/L5) (p < 0.05). There was a strong and inverse correlation between paraspinal muscle FF and trunk extension strength (ρ = −0.829, p < 0.001), gluteus maximus FF and hip extension strength (ρ = −0.701, p = 0.005), FF of the knee extensor muscles (quadriceps and sartorius) and knee extension strength (ρ = −0.842, p < 0.001), and FF of the knee flexor muscles (hamstring muscles) and knee flexion strength (ρ = −0.864, p < 0.001). Fat fraction of the paraspinal muscles also correlated with muscle FF of the thigh muscles and lower leg muscles.Conclusion: In conclusion, patients with Becker muscular dystrophy demonstrate severe paraspinal muscular involvement indicated by low back extension strength and high levels of fat replacement, which parallel involvement of lower limb muscles. Assessment of paraspinal muscle strength and fat replacement may serve as a possible biomarker for both the clinical management and further study of the disease.
- Published
- 2021
- Full Text
- View/download PDF
24. Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints
- Author
-
Alexander P. Murphy, Jasper Morrow, Julia R. Dahlqvist, Tanya Stojkovic, Tracey A. Willis, Christopher D. J. Sinclair, Stephen Wastling, Tarek Yousry, Michael S. Hanna, Meredith K. James, Anna Mayhew, Michelle Eagle, Laurence E. Lee, Jean‐Yves Hogrel, Pierre G. Carlier, John S. Thornton, John Vissing, Kieren G. Hollingsworth, and Volker Straub
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years. Methods Twenty‐three participants with LGMD R9, previously assessed over a 1‐year period, were re‐enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups. Results At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1‐year follow‐up study. In direct contrast to the 1‐year follow‐up, the 6‐min walk test, 10‐m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1‐ and 6‐year studies. Interpretation These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.
- Published
- 2019
- Full Text
- View/download PDF
25. Mitochondrial mutation m.3243A>G associates with insulin resistance in non-diabetic carriers
- Author
-
Jakob Høgild Langdahl, Anja Lisbeth Frederiksen, John Vissing, Morten Frost, Knud Bonnet Yderstræde, and Per Heden Andersen
- Subjects
monogenic diabetes ,G%22">mitochondrial DNA point mutation m.3243A>G ,mitochondrial dysfunction ,insulin resistance ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Aim: This case–control study aimed to examine impairments in glucose metabolism in non-diabetic carriers of the mitochondrial mutation m.3243A>G by evaluating insulin secretion capacity and sensitivity. Methods: Glucose metabolism was investigated in 23 non-diabetic m.3243A>G carriers and age-, sex- and BMI-matched healthy controls with an extended 4-h oral glucose tolerance test (OGTT). Insulin sensitivity index and acute insulin response were estimated on the basis of the OGTT. This was accompanied by examination of body composition by dual-energy X-ray absorptiometry (DXA), maximum aerobic capacity and a Recent Physical Activity Questionnaire (RPAQ). Results: Fasting p-glucose, s-insulin and s-c-peptide levels did not differ between m.3243A>G carriers and controls. Insulin sensitivity index (BIGTT-S1) was significantly lower in the m.3243A>G carriers, but there was no difference in the acute insulin response between groups. P-lactate levels were higher in carriers throughout the OGTT. VO2max, but not BMI, waist and hip circumferences, lean and fat body mass%, MET or grip strength, was lower in mutation carriers. BIGTT-S1 remained lower in mutation carriers after adjustment for multiple confounding factors including VO2max in regression analyses. Conclusions: Glucose metabolism in m.3243A>G carriers was characterized by reduced insulin sensitivity, which could represent the earliest phase in the pathogenesis of m.3243A>G-associated diabetes.
- Published
- 2019
- Full Text
- View/download PDF
26. High Resolution Analysis of DMPK Hypermethylation and Repeat Interruptions in Myotonic Dystrophy Type 1
- Author
-
Astrid Rasmussen, Mathis Hildonen, John Vissing, Morten Duno, Zeynep Tümer, and Ulf Birkedal
- Subjects
Oxford nanopore ,long-read sequencing ,DM1 ,epigenetics ,methylation ,diagnostics ,Genetics ,QH426-470 - Abstract
Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder caused by the expansion of a CTG repeat in the 3′-UTR of DMPK, which is transcribed to a toxic gain-of-function RNA that affects splicing of a range of genes. The expanded repeat is unstable in both germline and somatic cells. The variable age at disease onset and severity of symptoms have been linked to the inherited CTG repeat length, non-CTG interruptions, and methylation levels flanking the repeat. In general, the genetic biomarkers are investigated separately with specific methods, making it tedious to obtain an overall characterisation of the repeat for a given individual. In the present study, we employed Oxford nanopore sequencing in a pilot study to simultaneously determine the repeat lengths, investigate the presence and nature of repeat interruptions, and quantify methylation levels in the regions flanking the CTG-repeats in four patients with DM1. We determined the repeat lengths, and in three patients, we observed interruptions which were not detected using repeat-primed PCR. Interruptions may thus be more common than previously anticipated and should be investigated in larger cohorts. Allele-specific analyses enabled characterisation of aberrant methylation levels specific to the expanded allele, which greatly increased the sensitivity and resolved cases where the methylation levels were ambiguous.
- Published
- 2022
- Full Text
- View/download PDF
27. Quantitative Muscle MRI as Outcome Measure in Patients With Becker Muscular Dystrophy—A 1-Year Follow-Up Study
- Author
-
Aisha M. Sheikh, Karen Rudolf, Nanna Witting, and John Vissing
- Subjects
Becker muscular dystrophy ,quantitative muscle MRI ,muscle strength ,fat fraction ,outcome measure ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Introduction: With the advent of emerging molecular therapies for muscular dystrophies, the need for knowledge about natural history course of such diseases is of utmost importance in the preparation for future trials. However, for Becker muscular dystrophy such knowledge is scarce.Objective: In this 1-year follow-up study, we examined disease progression in Becker muscular dystrophy by monitoring changes in MRI-assessed muscle fat fraction (FF) in axial and lower limb muscles and quantitative muscle strength of axial muscles.Methods and Materials: Sixteen patients with Becker muscular dystrophy were investigated by (1) muscle strength of the trunk using a Biodex dynamometer and (2) Dixon muscle MRI of paraspinal and lower limb muscles. Quantitative MRI data was analyzed in two parts: The first part consisted of all participants (N = 16). The second analysis assessed two separate groups comprising lesser affected participants (N = 5) and more severely affected patients (n = 11).Results: Trunk extension and flexion strength remained stable from baseline to follow-up. MRI did not show any significant increase in muscle FF % from baseline to follow-up in all patients, except for multifidus at the spinal level T12 (p = 0.01). However, when we analyzed the two subgroups, according to disease severity, FF% increased in the lesser severely affected group at L4/L5 erector spinae (p = 0.047), sartorius (p = 0.028), gracilis (p = 0.009), tibialis anterior (p = 0.047), peroneals (p = 0.028), and gastrocnemius medialis (p = 0.009), while the severely affected group only increased significantly at T12 multifidus (p = 0.028) and T12 erector spinae (p = 0.011). No difference in muscle strength was observed in the two subgroups.Conclusion: Our results add to the existing knowledge about the natural rate of disease progression in BMD. As quantitative MRI was able to identify changes where strength assessment was not, MRI could be a strong biomarker for change in BMD. However, our findings show that it is important to stratify patients with BMD according to phenotype for future clinical trials.
- Published
- 2021
- Full Text
- View/download PDF
28. Mutation Load of Single, Large-Scale Deletions of mtDNA in Mitotic and Postmitotic Tissues
- Author
-
Tina D. Jeppesen, Morten Duno, and John Vissing
- Subjects
mtDNA mutation ,mtDNA deletion ,phenotype–genotype ,mitochondrial myopathy ,CPEO ,chronic progressive external ophthalmoplegia ,Genetics ,QH426-470 - Abstract
It is generally accepted that patients with chronic progressive ophthalmoplegia caused by single large-scale deletion (SLD) of mitochondrial DNA (mtDNA) only harbor mutation in skeletal and eye muscles. The aim of this study was to investigate the presence and the level of heteroplasmy of mtDNA deletions in mitotic tissues of patients displaying mtDNA deletion of mitotic tissues in patients with SLDs and pure muscle phenotype. MtDNA mutation load was studied in three mitotic (urine epithelial cells, buccal mucosa, and blood) and one postmitotic (skeletal muscle) tissues in 17 patients with SLDs of mtDNA and pure muscle involvement. All patients had mtDNA deletion in skeletal muscle, and 78% of the patients also displayed the mtDNA deletion in mitotic tissues. The mtDNA mutation load was higher in skeletal muscle versus mitotic tissues. The mtDNA mutation load did not correlate with age of sampling of tissues, but there was a correlation between the mtDNA mutations load in skeletal muscle and (1) the site of 5′ end breaking point of the SLD, (2) the size of SLD, (3) the number of affected tRNAs, and (4) age at onset (r > 0.58, P < 0.05). The findings indicate that mtDNA mutation in mitotic tissue is common in patients with SLDs of mtDNA. The lack of correlation between age of tissue sampling, age at onset, and mtDNA mutation load in mitotic tissues indicates that there is no extensive post-natal modification of mtDNA mutation load in mitotic tissues of patients with pure muscle phenotype.
- Published
- 2020
- Full Text
- View/download PDF
29. Growth Factors Do Not Improve Muscle Function in Young or Adult mdx Mice
- Author
-
Tue L. Nielsen, Tessa M. Hornsyld, Tomàs Pinós, Camilla Brolin, John Vissing, and Thomas O. Krag
- Subjects
mdx ,DMD ,muscular regeneration ,hepatocyte growth factor ,leukemia inhibitory factor ,Biology (General) ,QH301-705.5 - Abstract
Muscular dystrophies constitute a broad group of genetic disorders leading to muscle wasting. We have previously demonstrated that treating a muscular atrophy mouse model with growth factors resulted in increased muscle mass. In the present study, we treated the Duchenne mouse model mdx for 12 weeks with myogenic growth factors peri- and post-onset of muscular degeneration to explore the effects in the oxidative muscle soleus and the glycolytic muscle extensor digitorum longus (EDL). We found no overall beneficial effect in the peri-onset group at the conclusion of the study. In the post-onset group, the functional improvement by means of electrophysiological examinations ex vivo was mostly confined to the soleus. EDL benefitted from the treatment on a molecular level but did not improve functionally. Histopathology revealed signs of inflammation at the end of treatment. In conclusion, the growth factor cocktail failed to improve the mdx on a functional level.
- Published
- 2022
- Full Text
- View/download PDF
30. Absence of p.R50X Pygm read-through in McArdle disease cellular models
- Author
-
Guillermo Tarrasó, Alberto Real-Martinez, Marta Parés, Lídia Romero-Cortadellas, Laura Puigros, Laura Moya, Noemí de Luna, Astrid Brull, Miguel Angel Martín, Joaquin Arenas, Alejandro Lucia, Antoni L. Andreu, Jordi Barquinero, John Vissing, Thomas O. Krag, and Tomàs Pinós
- Subjects
mcardle disease ,metabolic myopathy ,premature termination codon ,read-through ,cellular models ,Medicine ,Pathology ,RB1-214 - Abstract
McArdle disease is an autosomal recessive disorder caused by the absence of muscle glycogen phosphorylase, which leads to blocked muscle glycogen breakdown. We used three different cellular models to evaluate the efficiency of different read-through agents (including amlexanox, Ataluren, RTC13 and G418) in McArdle disease. The first model consisted of HeLa cells transfected with two different GFP-PYGM constructs presenting the Pygm p.R50X mutation (GFP-PYGM p.R50X and PYGM Ex1-GFP p.R50X). The second cellular model was based on the creation of HEK293T cell lines stably expressing the PYGM Ex1-GFP p.R50X construct. As these plasmids encode murine Pygm cDNA without any intron sequence, their transfection in cells would allow for analysis of the efficacy of read-through agents with no concomitant nonsense-mediated decay interference. The third model consisted of skeletal muscle cultures derived from the McArdle mouse model (knock-in for the p.R50X mutation in the Pygm gene). We found no evidence of read-through at detectable levels in any of the models evaluated. We performed a literature search and compared the premature termination codon context sequences with reported positive and negative read-through induction, identifying a potential role for nucleotide positions −9, −8, −3, −2, +13 and +14 (the first nucleotide of the stop codon is assigned as +1). The Pygm p.R50X mutation presents TGA as a stop codon, G nucleotides at positions −1 and −9, and a C nucleotide at −3, which potentially generate a good context for read-through induction, counteracted by the presence of C at −2 and its absence at +4.
- Published
- 2020
- Full Text
- View/download PDF
31. Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness
- Author
-
Katherine Johnson, Marta Bertoli, Lauren Phillips, Ana Töpf, Peter Van den Bergh, John Vissing, Nanna Witting, Shahriar Nafissi, Shirin Jamal-Omidi, Anna Łusakowska, Anna Kostera-Pruszczyk, Anna Potulska-Chromik, Nicolas Deconinck, Carina Wallgren-Pettersson, Sonja Strang-Karlsson, Jaume Colomer, Kristl G. Claeys, Willem De Ridder, Jonathan Baets, Maja von der Hagen, Roberto Fernández-Torrón, Miren Zulaica Ijurco, Juan Bautista Espinal Valencia, Andreas Hahn, Hacer Durmus, Tracey Willis, Liwen Xu, Elise Valkanas, Thomas E. Mullen, Monkol Lek, Daniel G. MacArthur, and Volker Straub
- Subjects
Whole-exome sequencing ,Dystroglycanopathies ,Limb-girdle muscle weakness ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. Methods Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. Results Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. Conclusions Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.
- Published
- 2018
- Full Text
- View/download PDF
32. Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies
- Author
-
Mónica Villarreal-Salazar, Astrid Brull, Gisela Nogales-Gadea, Antoni L. Andreu, Miguel A. Martín, Joaquín Arenas, Alfredo Santalla, Alejandro Lucia, John Vissing, Thomas O. Krag, and Tomàs Pinós
- Subjects
McArdle disease ,glycogen ,glycogen phosphorylase ,research models ,treatments ,Genetics ,QH426-470 - Abstract
McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute “crises” of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient’s phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients.
- Published
- 2021
- Full Text
- View/download PDF
33. Pure exercise intolerance and ophthalmoplegia associated with the m.12,294G > A mutation in the MT-TL2 gene: a case report
- Author
-
Patrick Soldath, Karen Lindhardt Madsen, Astrid Emilie Buch, Morten Duno, Flemming Wibrand, and John Vissing
- Subjects
Case report ,Mitochondrial DNA ,MT-TL2 mutation ,Mitochondrial myopathy ,Exercise intolerance ,Exercise physiological study ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Pure exercise intolerance associated with exclusive affection of skeletal muscle is a very rare phenotype of patients with mitochondrial myopathy. Moreover, the exercise intolerance in these rare patients is yet not well explored, as most of known cases have not been assessed by objective testing, but only by interview. We report a patient with a mitochondrial DNA (mtDNA) mutation that gives rise to an exclusive myopathy associated with exercise intolerance and ophthalmoplegia. We quantified the patient’s exercise intolerance through detailed exercise testing. Case presentation A 39-year-old man presented with exercise intolerance and chronic progressive external ophthalmoplegia. Sequencing of the entire mtDNA identified a m.12,294G > A mutation in the MT-TL2 gene. The mutation was heteroplasmic in skeletal muscle (75%) while undetectable in blood, urinary sediment, and buccal mucosa as well as in tissues from the patient’s mother. The mutation affected a highly conserved site in the anticodon stem of the mitochondrial transfer RNA Leucine (CUN) molecule and lead to a severe combined respiratory chain defect. Exercise physiological studies in the patient demonstrated a significantly reduced maximal oxygen uptake of 20.4 ml O2 × min−1 × kg−1 (about half of normal) as well as threefold elevated lactate/pyruvate ratios. Conclusion The findings of our study support that the m.12,294G > A mutation is pathogenic. Likely, the mutation arose sporadically in early embryogenesis after differentiation of the mesoderm into muscle progenitor cells, leading to a pure myopathic phenotype.
- Published
- 2017
- Full Text
- View/download PDF
34. Exercise Testing, Physical Training and Fatigue in Patients with Mitochondrial Myopathy Related to mtDNA Mutations
- Author
-
Tina D. Jeppesen, Karen L. Madsen, Nanna S. Poulsen, Nicoline Løkken, and John Vissing
- Subjects
mitochondrial myopathy ,mtDNA mutation ,exercise testing ,fatigue ,Medicine - Abstract
Mutations in mitochondrial DNA (mtDNA) cause disruption of the oxidative phosphorylation chain and impair energy production in cells throughout the human body. Primary mitochondrial disorders due to mtDNA mutations can present with symptoms from adult-onset mono-organ affection to death in infancy due to multi-organ involvement. The heterogeneous phenotypes that patients with a mutation of mtDNA can present with are thought, at least to some extent, to be a result of differences in mtDNA mutation load among patients and even among tissues in the individual. The most common symptom in patients with mitochondrial myopathy (MM) is exercise intolerance. Since mitochondrial function can be assessed directly in skeletal muscle, exercise studies can be used to elucidate the physiological consequences of defective mitochondria due to mtDNA mutations. Moreover, exercise tests have been developed for diagnostic purposes for mitochondrial myopathy. In this review, we present the rationale for exercise testing of patients with MM due to mutations in mtDNA, evaluate the diagnostic yield of exercise tests for MM and touch upon how exercise tests can be used as tools for follow-up to assess disease course or effects of treatment interventions.
- Published
- 2021
- Full Text
- View/download PDF
35. Skeletal muscle metabolism during prolonged exercise in Pompe disease
- Author
-
Nicolai Preisler, Pascal Laforêt, Karen Lindhardt Madsen, Edith Husu, Christoffer Rasmus Vissing, Gitte Hedermann, Henrik Galbo, Christopher Lindberg, and John Vissing
- Subjects
skeletal muscle metabolism ,glycogen ,exercise ,Pompe disease ,glycogenosis ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Objective: Pompe disease (glycogenosis type II) is caused by lysosomal alpha-glucosidase deficiency, which leads to a block in intra-lysosomal glycogen breakdown. In spite of enzyme replacement therapy, Pompe disease continues to be a progressive metabolic myopathy. Considering the health benefits of exercise, it is important in Pompe disease to acquire more information about muscle substrate use during exercise. Methods: Seven adults with Pompe disease were matched to a healthy control group (1:1). We determined (1) peak oxidative capacity (VO2peak) and (2) carbohydrate and fatty acid metabolism during submaximal exercise (33 W) for 1 h, using cycle-ergometer exercise, indirect calorimetry and stable isotopes. Results: In the patients, VO2peak was less than half of average control values; mean difference −1659 mL/min (CI: −2450 to −867, P = 0.001). However, the respiratory exchange ratio increased to >1.0 and lactate levels rose 5-fold in the patients, indicating significant glycolytic flux. In line with this, during submaximal exercise, the rates of oxidation (ROX) of carbohydrates and palmitate were similar between patients and controls (mean difference 0.226 g/min (CI: 0.611 to −0.078, P = 0.318) and mean difference 0.016 μmol/kg/min (CI: 1.287 to −1.255, P = 0.710), respectively). Conclusion: Reflecting muscle weakness and wasting, Pompe disease is associated with markedly reduced maximal exercise capacity. However, glycogenolysis is not impaired in exercise. Unlike in other metabolic myopathies, skeletal muscle substrate use during exercise is normal in Pompe disease rendering exercise less complicated for e.g. medical or recreational purposes.
- Published
- 2017
- Full Text
- View/download PDF
36. Antimyostatin Treatment in Health and Disease: The Story of Great Expectations and Limited Success
- Author
-
Tue L. Nielsen, John Vissing, and Thomas O. Krag
- Subjects
myostatin ,muscular dystrophy ,muscular regeneration ,ActRIIB ,TGF-β ,Cytology ,QH573-671 - Abstract
In the past 20 years, myostatin, a negative regulator of muscle mass, has attracted attention as a potential therapeutic target in muscular dystrophies and other conditions. Preclinical studies have shown potential for increasing muscular mass and ameliorating the pathological features of dystrophic muscle by the inhibition of myostatin in various ways. However, hardly any clinical trials have proven to translate the promising results from the animal models into patient populations. We present the background for myostatin regulation, clinical and preclinical results and discuss why translation from animal models to patients is difficult. Based on this, we put the clinical relevance of future antimyostatin treatment into perspective.
- Published
- 2021
- Full Text
- View/download PDF
37. Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models
- Author
-
Aitana Almodóvar-Payá, Mónica Villarreal-Salazar, Noemí de Luna, Gisela Nogales-Gadea, Alberto Real-Martínez, Antoni L. Andreu, Miguel Angel Martín, Joaquin Arenas, Alejandro Lucia, John Vissing, Thomas Krag, and Tomàs Pinós
- Subjects
glycogen storage diseases ,animal models ,therapy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
GSD are a group of disorders characterized by a defect in gene expression of specific enzymes involved in glycogen breakdown or synthesis, commonly resulting in the accumulation of glycogen in various tissues (primarily the liver and skeletal muscle). Several different GSD animal models have been found to naturally present spontaneous mutations and others have been developed and characterized in order to further understand the physiopathology of these diseases and as a useful tool to evaluate potential therapeutic strategies. In the present work we have reviewed a total of 42 different animal models of GSD, including 26 genetically modified mouse models, 15 naturally occurring models (encompassing quails, cats, dogs, sheep, cattle and horses), and one genetically modified zebrafish model. To our knowledge, this is the most complete list of GSD animal models ever reviewed. Importantly, when all these animal models are analyzed together, we can observe some common traits, as well as model specific differences, that would be overlooked if each model was only studied in the context of a given GSD.
- Published
- 2020
- Full Text
- View/download PDF
38. Effect of Aerobic Exercise Training and Deconditioning on Oxidative Capacity and Muscle Mitochondrial Enzyme Machinery in Young and Elderly Individuals
- Author
-
Andreas Mæchel Fritzen, Søren Peter Andersen, Khaled Abdul Nasser Qadri, Frank D. Thøgersen, Thomas Krag, Mette C. Ørngreen, John Vissing, and Tina D. Jeppesen
- Subjects
aerobic exercise training ,mitochondria ,sarcopenia ,endurance ,deconditioning ,skeletal muscle ,Medicine - Abstract
Mitochondrial dysfunction is thought to be involved in age-related loss of muscle mass and function (sarcopenia). Since the degree of physical activity is vital for skeletal muscle mitochondrial function and content, the aim of this study was to investigate the effect of 6 weeks of aerobic exercise training and 8 weeks of deconditioning on functional parameters of aerobic capacity and markers of muscle mitochondrial function in elderly compared to young individuals. In 11 healthy, elderly (80 ± 4 years old) and 10 healthy, young (24 ± 3 years old) volunteers, aerobic training improved maximal oxygen consumption rate by 13%, maximal workload by 34%, endurance capacity by 2.4-fold and exercise economy by 12% in the elderly to the same extent as in young individuals. This evidence was accompanied by a similar training-induced increase in muscle citrate synthase (CS) (31%) and mitochondrial complex I–IV activities (51–163%) in elderly and young individuals. After 8 weeks of deconditioning, endurance capacity (−20%), and enzyme activity of CS (−18%) and complex I (−40%), III (−25%), and IV (−26%) decreased in the elderly to a larger extent than in young individuals. In conclusion, we found that elderly have a physiological normal ability to improve aerobic capacity and mitochondrial function with aerobic training compared to young individuals, but had a faster decline in endurance performance and muscle mitochondrial enzyme activity after deconditioning, suggesting an age-related issue in maintaining oxidative metabolism.
- Published
- 2020
- Full Text
- View/download PDF
39. Age-Associated Salivary MicroRNA Biomarkers for Oculopharyngeal Muscular Dystrophy
- Author
-
Vered Raz, Rosemarie H. M. J. M. Kroon, Hailiang Mei, Muhammad Riaz, Henk Buermans, Saskia Lassche, Corinne Horlings, Bert De Swart, Johanna Kalf, Pradeep Harish, John Vissing, Szymon Kielbasa, and Baziel G. M. van Engelen
- Subjects
OPMD ,miRNA ,muscle aging ,muscle atrophy ,circulating miRNA ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Small non-coding microRNAs (miRNAs) are involved in the regulation of mRNA stability. Their features, including high stability and secretion to biofluids, make them attractive as potential biomarkers for diverse pathologies. This is the first study reporting miRNA as potential biomarkers for oculopharyngeal muscular dystrophy (OPMD), an adult-onset myopathy. We hypothesized that miRNA that is differentially expressed in affected muscles from OPMD patients is secreted to biofluids and those miRNAs could be used as biomarkers for OPMD. We first identified candidate miRNAs from OPMD-affected muscles and from muscles from an OPMD mouse model using RNA sequencing. We then compared the OPMD-deregulated miRNAs to the literature and, subsequently, we selected a few candidates for expression studies in serum and saliva biofluids using qRT-PCR. We identified 126 miRNAs OPMD-deregulated in human muscles, but 36 deregulated miRNAs in mice only (pFDR < 0.05). Only 15 OPMD-deregulated miRNAs overlapped between the in humans and mouse studies. The majority of the OPMD-deregulated miRNAs showed opposite deregulation direction compared with known muscular dystrophies miRNAs (myoMirs), which are associated. In contrast, similar dysregulation direction was found for 13 miRNAs that are common between OPMD and aging muscles. A significant age-association (p < 0.05) was found for 17 OPMD-deregulated miRNAs (13.4%), whereas in controls, only six miRNAs (1.4%) showed a significant age-association, suggesting that miRNA expression in OPMD is highly age-associated. miRNA expression in biofluids revealed that OPMD-associated deregulation in saliva was similar to that in muscles, but not in serum. The same as in muscle, miRNA expression levels in saliva were also found to be associated with age (p < 0.05). Moreover, the majority of OPMD-miRNAs were found to be associated with dysphagia as an initial symptom. We suggest that levels of specific miRNAs in saliva can mark muscle degeneration in general and dysphagia in OPMD.
- Published
- 2020
- Full Text
- View/download PDF
40. Stable Longitudinal Methylation Levels at the CpG Sites Flanking the CTG Repeat of DMPK in Patients with Myotonic Dystrophy Type 1
- Author
-
Mathis Hildonen, Kirsten Lykke Knak, Morten Dunø, John Vissing, and Zeynep Tümer
- Subjects
epigenetics ,genetics ,trinucleotide ,repeat ,inheritance ,blood ,Genetics ,QH426-470 - Abstract
Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disorder mainly characterized by gradual muscle loss, weakness, and delayed relaxation after muscle contraction. It is caused by an expanded CTG repeat in the 3′ UTR of DMPK, which is transcribed into a toxic gain-of-function mRNA that affects the splicing of a range of other genes. The repeat is unstable, with a bias towards expansions both in somatic cells and in the germline, which results in a tendency for earlier onset with each generation, as longer repeat lengths generally correlate with earlier onset. Previous studies have found hypermethylation in the regions flanking the repeat in congenital onset DM1 and in some patients with non-congenital DM1. We used pyrosequencing to investigate blood methylation levels in 68 patients with non-congenital DM1, compare the methylation levels between the blood and muscle, and assess whether methylation levels change over time in the blood. We found higher methylation levels in the blood of DM1 patients than in healthy controls and especially in the patients who had inherited the disease allele maternally. The methylation levels remained relatively stable over time and are a strong biomarker of the disease, as well as of the maternal inheritance of the disease.
- Published
- 2020
- Full Text
- View/download PDF
41. Preserved Capacity for Adaptations in Strength and Muscle Regulatory Factors in Elderly in Response to Resistance Exercise Training and Deconditioning
- Author
-
Andreas Mæchel Fritzen, Frank D. Thøgersen, Khaled Abdul Nasser Qadri, Thomas Krag, Marie-Louise Sveen, John Vissing, and Tina D. Jeppesen
- Subjects
resistance exercise training ,muscle regulatory factors ,sarcopenia ,muscle strength ,deconditioning ,skeletal muscle ,Medicine - Abstract
Aging is related to an inevitable loss of muscle mass and strength. The mechanisms behind age-related loss of muscle tissue are not fully understood but may, among other things, be induced by age-related differences in myogenic regulatory factors. Resistance exercise training and deconditioning offers a model to investigate differences in myogenic regulatory factors that may be important for age-related loss of muscle mass and strength. Nine elderly (82 ± 7 years old) and nine young, healthy persons (22 ± 2 years old) participated in the study. Exercise consisted of six weeks of resistance training of the quadriceps muscle followed by eight weeks of deconditioning. Muscle biopsy samples before and after training and during the deconditioning period were analyzed for MyoD, myogenin, insulin-like growth-factor I receptor, activin receptor IIB, smad2, porin, and citrate synthase. Muscle strength improved with resistance training by 78% (95.0 ± 22.0 kg) in the elderly to a similar extent as in the young participants (83.5%; 178.2 ± 44.2 kg) and returned to baseline in both groups after eight weeks of deconditioning. No difference was seen in expression of muscle regulatory factors between elderly and young in response to exercise training and deconditioning. In conclusion, the capacity to gain muscle strength with resistance exercise training in elderly was not impaired, highlighting this as a potent tool to combat age-related loss of muscle function, possibly due to preserved regulation of myogenic factors in elderly compared with young muscle.
- Published
- 2020
- Full Text
- View/download PDF
42. Adaptations in Mitochondrial Enzymatic Activity Occurs Independent of Genomic Dosage in Response to Aerobic Exercise Training and Deconditioning in Human Skeletal Muscle
- Author
-
Andreas M. Fritzen, Frank B. Thøgersen, Kasper Thybo, Christoffer R. Vissing, Thomas O. Krag, Cristina Ruiz-Ruiz, Lotte Risom, Flemming Wibrand, Louise D. Høeg, Bente Kiens, Morten Duno, John Vissing, and Tina D. Jeppesen
- Subjects
mtDNA ,mitochondria ,skeletal muscle ,exercise training ,mitochondrial biogenesis ,Cytology ,QH573-671 - Abstract
Mitochondrial DNA (mtDNA) replication is thought to be an integral part of exercise-training-induced mitochondrial adaptations. Thus, mtDNA level is often used as an index of mitochondrial adaptations in training studies. We investigated the hypothesis that endurance exercise training-induced mitochondrial enzymatic changes are independent of genomic dosage by studying mtDNA content in skeletal muscle in response to six weeks of knee-extensor exercise training followed by four weeks of deconditioning in one leg, comparing results to the contralateral untrained leg, in 10 healthy, untrained male volunteers. Findings were compared to citrate synthase activity, mitochondrial complex activities, and content of mitochondrial membrane markers (porin and cardiolipin). One-legged knee-extensor exercise increased endurance performance by 120%, which was accompanied by increases in power output and peak oxygen uptake of 49% and 33%, respectively (p < 0.01). Citrate synthase and mitochondrial respiratory chain complex I–IV activities were increased by 51% and 46–61%, respectively, in the trained leg (p < 0.001). Despite a substantial training-induced increase in mitochondrial activity of TCA and ETC enzymes, there was no change in mtDNA and mitochondrial inner and outer membrane markers (i.e. cardiolipin and porin). Conversely, deconditioning reduced endurance capacity by 41%, muscle citrate synthase activity by 32%, and mitochondrial complex I–IV activities by 29–36% (p < 0.05), without any change in mtDNA and porin and cardiolipin content in the previously trained leg. The findings demonstrate that the adaptations in mitochondrial enzymatic activity after aerobic endurance exercise training and the opposite effects of deconditioning are independent of changes in the number of mitochondrial genomes, and likely relate to changes in the rate of transcription of mtDNA.
- Published
- 2019
- Full Text
- View/download PDF
43. Aerobic Training in Patients with Congenital Myopathy.
- Author
-
Gitte Hedermann, Christoffer Rasmus Vissing, Karen Heje, Nicolai Preisler, Nanna Witting, and John Vissing
- Subjects
Medicine ,Science - Abstract
INTRODUCTION:Congenital myopathies (CM) often affect contractile proteins of the sarcomere, which could render patients susceptible to exercise-induced muscle damage. We investigated if exercise is safe and beneficial in patients with CM. METHODS:Patients exercised on a stationary bike for 30 minutes, three times weekly, for 10 weeks at 70% of their maximal oxygen uptake (VO2max). Creatine kinase (CK) was monitored as a marker of muscle damage. VO2max, functional tests, and questionnaires evaluated efficacy. RESULTS:Sixteen patients with CM were included in a controlled study. VO2max increased by 14% (range, 6-25%; 95% CI 7-20; p < 0.001) in the seven patients who completed training, and tended to decrease in a non-intervention group (n = 7; change -3.5%; range, -11-3%, p = 0.083). CK levels were normal and remained stable during training. Baseline Fatigue Severity Scale scores were high, 4.9 (SE 1.9), and tended to decrease (to 4.4 (SE 1.7); p = 0.08) with training. Nine patients dropped out of the training program. Fatigue was the major single reason. CONCLUSIONS:Ten weeks of endurance training is safe and improves fitness in patients with congenital myopathies. The training did not cause sarcomeric injury, even though sarcomeric function is affected by the genetic abnormalities in most patients with CM. Severe fatigue, which characterizes patients with CM, is a limiting factor for initiating training in CM, but tends to improve in those who train. TRIAL REGISTRATION:The Regional Committee on Health Research Ethics of the Capital Region of Denmark H-2-2013-066 and ClinicalTrials.gov H2-2013-066.
- Published
- 2016
- Full Text
- View/download PDF
44. Effect of Gender, Disease Duration and Treatment on Muscle Strength in Myasthenia Gravis.
- Author
-
Gülsenay Citirak, Sanja Cejvanovic, Henning Andersen, and John Vissing
- Subjects
Medicine ,Science - Abstract
The aim of this observational, cross-sectional study was to quantify the potential presence of muscle weakness among patients with generalized myasthenia gravis (gMG). The influence of gender, treatment intensity and disease duration on muscle strength and disease progression was also assessed.Muscle strength was tested in 8 muscle groups by manual muscle testing and by hand-held dynamometry in 107 patients with gMG and 89 healthy age- and gender-matched controls. Disease duration, severity and treatment history were reviewed and compared with muscle strength.Patients had reduced strength in all tested muscle group compared to control subjects (p
- Published
- 2016
- Full Text
- View/download PDF
45. Decreased variability of the 6-minute walk test by heart rate correction in patients with neuromuscular disease.
- Author
-
Kira P Prahm, Nanna Witting, and John Vissing
- Subjects
Medicine ,Science - Abstract
OBJECTIVE: The 6-minute walk test is widely used to assess functional status in neurological disorders. However, the test is subject to great inter-test variability due to fluctuating motivation, fatigue and learning effects. We investigated whether inter-test variability of the 6MWT can be reduced by heart rate correction. METHODS: Sixteen patients with neuromuscular diseases, including Facioscapulohumeral muscular dystrophy, Limb-girdle muscular dystrophy, Charcot-Marie-Tooths, Dystrophia Myotonica and Congenital Myopathy and 12 healthy subjects were studied. Patients were excluded if they had cardiac arrhythmias, if they received drug treatment for hypertension or any other medical conditions that could interfere with the interpretation of the heart rate and walking capability. All completed three 6-minute walk tests on three different test-days. Heart rate was measured continuously. RESULTS: Successive standard 6-minute walk tests showed considerable learning effects between Tests 1 and 2 (4.9%; P = 0.026), and Tests 2 and 3 (4.5%; P = 0.020) in patients. The same was seen in controls between Tests 1 and 2 (8.1%; P = 0.039)). Heart rate correction abolished this learning effect. CONCLUSION: A modified 6-minute walk test, by correcting walking distance with average heart rate during walking, decreases the variability among repeated 6-minute walk tests, and should be considered as an alternative outcome measure to the standard 6-minute walk test in future clinical follow-up and treatment trials.
- Published
- 2014
- Full Text
- View/download PDF
46. Quantitative magnetic resonance imaging in limb-girdle muscular dystrophy 2I: a multinational cross-sectional study.
- Author
-
Tracey A Willis, Kieren G Hollingsworth, Anna Coombs, Marie-Louise Sveen, Soren Andersen, Tanya Stojkovic, Michelle Eagle, Anna Mayhew, Paulo Loureiro de Sousa, Liz Dewar, Jasper M Morrow, Christopher D J Sinclair, John S Thornton, Kate Bushby, Hanns Lochmuller, Michael G Hanna, Jean-Yves Hogrel, Pierre G Carlier, John Vissing, and Volker Straub
- Subjects
Medicine ,Science - Abstract
We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (FKRP) gene were recruited. In each patient, T1-weighted (T1w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p
- Published
- 2014
- Full Text
- View/download PDF
47. Muscle atrophy reversed by growth factor activation of satellite cells in a mouse muscle atrophy model.
- Author
-
Simon Hauerslev, John Vissing, and Thomas O Krag
- Subjects
Medicine ,Science - Abstract
Muscular dystrophies comprise a large group of inherited disorders that lead to progressive muscle wasting. We wanted to investigate if targeting satellite cells can enhance muscle regeneration and thus increase muscle mass. We treated mice with hepatocyte growth factor and leukemia inhibitory factor under three conditions: normoxia, hypoxia and during myostatin deficiency. We found that hepatocyte growth factor treatment led to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myognic transcription factors MyoD and myogenin, and subsequently the negative growth control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we demonstrated that myostatin regulates satellite cell activation and myogenesis in vivo following treatment, consistent with previous findings in vitro. Our results suggest, not only a novel in vivo pharmacological treatment directed specifically at activating the satellite cells, but also a myostatin dependent mechanism that may contribute to the progressive muscle wasting seen in severely affected patients with muscular dystrophy and significant on-going regeneration. This treatment could potentially be applied to many conditions that feature muscle wasting to increase muscle bulk and strength.
- Published
- 2014
- Full Text
- View/download PDF
48. Quantitative muscle MRI as an assessment tool for monitoring disease progression in LGMD2I: a multicentre longitudinal study.
- Author
-
Tracey A Willis, Kieren G Hollingsworth, Anna Coombs, Marie-Louise Sveen, Søren Andersen, Tanya Stojkovic, Michelle Eagle, Anna Mayhew, Paulo L de Sousa, Liz Dewar, Jasper M Morrow, Christopher D J Sinclair, John S Thornton, Kate Bushby, Hanns Lochmüller, Michael G Hanna, Jean-Yves Hogrel, Pierre G Carlier, John Vissing, and Volker Straub
- Subjects
Medicine ,Science - Abstract
Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups.To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period.32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C>A mutation in the fukutin-related protein gene (FKRP) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale.There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T₁w images.Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.
- Published
- 2013
- Full Text
- View/download PDF
49. Protein turnover and cellular stress in mildly and severely affected muscles from patients with limb girdle muscular dystrophy type 2I.
- Author
-
Simon Hauerslev, Marie L Sveen, John Vissing, and Thomas O Krag
- Subjects
Medicine ,Science - Abstract
Patients with Limb girdle muscular dystrophy type 2I (LGMD2I) are characterized by progressive muscle weakness and wasting primarily in the proximal muscles, while distal muscles often are spared. Our aim was to investigate if wasting could be caused by impaired regeneration in the proximal compared to distal muscles. Biopsies were simultaneously obtained from proximal and distal muscles of the same patients with LGMD2I (n = 4) and healthy subjects (n = 4). The level of past muscle regeneration was evaluated by counting internally nucleated fibers and determining actively regenerating fibers by using the developmental markers embryonic myosin heavy chain (eMHC) and neural cell adhesion molecule (NCAM) and also assessing satellite cell activation status by myogenin positivity. Severe muscle histopathology was occasionally observed in the proximal muscles of patients with LGMD2I whereas distal muscles were always relatively spared. No difference was found in the regeneration markers internally nucleated fibers, actively regenerating fibers or activation status of satellite cells between proximal and distal muscles. Protein turnover, both synthesis and breakdown, as well as cellular stress were highly increased in severely affected muscles compared to mildly affected muscles. Our results indicate that alterations in the protein turnover and myostatin levels could progressively impair the muscle mass maintenance and/or regeneration resulting in gradual muscular atrophy.
- Published
- 2013
- Full Text
- View/download PDF
50. Rozanolixizumab efficacy in generalised myasthenia gravis: Subgroup analyses from the randomised, phase 3, MycarinG study
- Author
-
Jo, Moxey, primary, Artur, Drużdż, additional, Julian, Grosskreutz, additional, Renato, Mantegazza, additional, Kimiaki, Utsugisawa, additional, John, Vissing, additional, Raphaëlle Beau, Lejdstrom, additional, Marion, Boehnlein, additional, Fiona, Grimson, additional, and Vera, Bril, additional
- Published
- 2023
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.