glycogen and Glycogen-Storage-Disease-Type-V

Glycogen phosphorylase (PG) is a key enzyme taking part in the first step of glycogenolysis. Muscle glycogen phosphorylase (PYGM) differs from other PG isoforms in expression pattern and biochemical properties. The main role of PYGM is providing sufficient energy for muscle contraction. However, it is expressed in tissues other than muscle, such as the brain, lymphoid tissues, and blood. PYGM is important not only in glycogen metabolism, but also in such diverse processes as the insulin and glucagon signaling pathway, insulin resistance, necroptosis, immune response, and phototransduction. PYGM is implicated in several pathological states, such as muscle glycogen phosphorylase deficiency (McArdle disease), schizophrenia, and cancer. Here we attempt to analyze the available data regarding the protein partners of PYGM to shed light on its possible interactions and functions. We also underline the potential for zebrafish to become a convenient and applicable model to study PYGM functions, especially because of its unique features that can complement data obtained from other approaches.

Topics: Animals; Disease Models, Animal; Gene Expression Regulation; Glycogen; Glycogen Phosphorylase; Glycogen Storage Disease Type V; Humans; Insulin Resistance; Light Signal Transduction; Muscle Contraction; Muscle, Skeletal; Necroptosis; Neoplasms; Protein Interaction Mapping; Retinal Pigment Epithelium; Schizophrenia; Zebrafish

McArdle disease (glycogen storage disease type V) is caused by inherited deficiency of a key enzyme in muscle metabolism, the skeletal muscle-specific isoform of glycogen phosphorylase, "myophosphorylase," which is encoded by the PYGM gene. Here we review the main pathophysiological, genotypic, and phenotypic features of McArdle disease and their interactions. To date, moderate-intensity exercise (together with pre-exercise carbohydrate ingestion) is the only treatment option that has proven useful for these patients. Furthermore, regular physical activity attenuates the clinical severity of McArdle disease. This is quite remarkable for a monogenic disorder that consistently leads to the same metabolic defect at the muscle tissue level, that is, complete inability to use muscle glycogen stores. Further knowledge of this disorder would help patients and enhance understanding of exercise metabolism as well as exercise genomics. Indeed, McArdle disease is a paradigm of human exercise intolerance and PYGM genotyping should be included in the genetic analyses that might be applied in the coming personalized exercise medicine as well as in future research on genetics and exercise-related phenotypes.

Topics: Adolescent; Adult; Biopsy; Exercise; Exercise Tolerance; Female; Genotype; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Male; Middle Aged; Muscle, Skeletal; Muscles; Mutation; Phenotype; Registries; Spain

McArdle disease is arguably the paradigm of exercise intolerance in humans. This disorder is caused by inherited deficiency of myophosphorylase, the enzyme isoform that initiates glycogen breakdown in skeletal muscles. Because patients are unable to obtain energy from their muscle glycogen stores, this disease provides an interesting model of study for exercise physiologists, allowing insight to be gained into the understanding of glycogen-dependent muscle functions. Of special interest in the field of muscle physiology and sports medicine are also some specific (if not unique) characteristics of this disorder, such as the so-called 'second wind' phenomenon, the frequent exercise-induced rhabdomyolysis and myoglobinuria episodes suffered by patients (with muscle damage also occurring under basal conditions), or the early appearance of fatigue and contractures, among others. In this article we review the main pathophysiological features of this disorder leading to exercise intolerance as well as the currently available therapeutic possibilities. Patients have been traditionally advised by clinicians to refrain from exercise, yet sports medicine and careful exercise prescription are their best allies at present because no effective enzyme replacement therapy is expected to be available in the near future. As of today, although unable to restore myophosphorylase deficiency, the 'simple' use of exercise as therapy seems probably more promising and practical for patients than more 'complex' medical approaches.

Topics: Animals; Disease Models, Animal; Exercise Tolerance; Glycogen; Glycogen Storage Disease Type V; Glycogen Synthase; Humans; Models, Biological; Muscle Fatigue; Muscle, Skeletal; Physical Exertion; Rhabdomyolysis; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sports Medicine

Topics: Carbohydrate Metabolism; Carbohydrate Metabolism, Inborn Errors; Fructose-Bisphosphate Aldolase; Glycogen; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type IV; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VII; Glycogen Storage Disease Type VIII; Humans; L-Lactate Dehydrogenase; Mitochondrial Myopathies; Phosphoglycerate Kinase; Phosphoglycerate Mutase; Phosphorylase b

Topics: Diagnosis, Differential; Electromyography; Glucagon; Glucose; Glycogen; Glycogen Storage Disease Type V; Humans; Infusions, Intravenous; Mass Screening; Mutation; Purines

The molecular heterogeneities of enzyme abnormality have been identified successfully since 1990 for major clinical entities of glycogenolytic and glycolytic defects in skeletal muscle. The interchange between clinical medicine and basic science, which enabled these achievements, has a long history. This review introduces several important examples of this interchange, which has borne much fruit in the comprehensive understanding of glycogenolysis-glycolysis in skeletal muscle and the related defects that cause various metabolic diseases. For instance, the presence of "glycogen synthase" was mainly suggested by the pathophysiology of McArdle's disease. Clinical manifestations of muscle phosphofructokinase (PFK) deficiency have indicated that there could be PFK isozymes under separate genetic control. Although glycolysis is a unidirectional pathway, enzyme defects at each step do not necessarily cause similar manifestations. Glycogen accumulation is mostly associated with enzyme defects in glycogenolysis and in the first stage of glycolysis. Since the original report of phosphoglycerate mutase deficiency in 1981, no newly recognized glycolytic defects have been presented. Glycolytic steps for which no enzyme deficiency has been identified seem to provide another important impetus for further study of "fail-safe" mechanisms in regard to monogenic disorders.

Topics: Biochemical Phenomena; Biochemistry; Clinical Medicine; Fructosediphosphates; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Humans; Isoenzymes; Muscular Diseases; Phosphofructokinase-1; Phosphoglycerate Kinase

Topics: Amino Acid Sequence; Animals; Base Sequence; Glycogen; Glycogen Storage Disease Type V; Glycolysis; Humans; Molecular Sequence Data; Muscle, Skeletal; Mutation; Phosphorylases

Muscle phosphorylase deficiency (McArdle's disease) has conventionally been considered a disorder of glycogenolysis, and the associated impairment in oxidative metabolism has been largely overlooked. Muscle glycogen normally is the primary oxidative fuel at exercise work loads requiring more than 75-80% of maximal O2 uptake (VO2max). Evidence is presented to support the hypothesis that a limited flux through the Embden-Myerhof pathway in McArdle's disease reduces the capacity to generate NADH required to support a normal VO2max. The extent of the oxidative defect is substrate dependent; i.e., it can be partially corrected by increasing the availability of alternative oxidative substrates (e.g., glucose, free fatty acids) to working muscle. Experiments employing modification of substrate availability closely link the hyperkinetic circulatory response to exercise (i.e., an abnormally large increase in O2 transport to skeletal muscle) and the premature muscle fatigue and cramping of McArdle patients with their oxidative impairment and suggest that a metabolic common denominator in these abnormal responses may be a pronounced decline in the muscle phosphorylation potential ([ATP]/[ADP][Pi]). The hyperkinetic circulation likely is mediated by the local effects on metabolically sensitive skeletal muscle afferents and vascular smooth muscle of K+, Pi, or adenosine or a combination of these substances released excessively from working skeletal muscle. The premature muscle fatigue and cramping of McArdle patients does not appear to be due to depletion of ATP but is associated with an increased accumulation of Pi and probably ADP in skeletal muscle. Accumulations of Pi and ADP are known to inhibit the myofibrillar, Ca2+, and Na+-K+-ATPase reactions.

Topics: Biological Availability; Biological Transport; Biomechanical Phenomena; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Humans; Muscles; Oxidation-Reduction; Oxygen Consumption; Physical Exertion

Topics: alpha-Glucosidases; AMP Deaminase; Carnitine; Carnitine O-Palmitoyltransferase; Creatine Kinase; Female; Glucan 1,4-alpha-Glucosidase; Glycogen; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VII; Humans; Lipid Metabolism, Inborn Errors; Male; Metabolism, Inborn Errors; Muscular Diseases; Phosphofructokinase-1; Phosphorylase a

Topics: 1,4-alpha-Glucan Branching Enzyme; Animals; Bacteria; Biodegradation, Environmental; Chick Embryo; Chickens; Glucosidases; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VI; Glycogen Storage Disease Type VII; Goats; Humans; Liver; Mice; Mutation; Rabbits; Sugar Phosphates

Two single case studies suggest that a protein-rich diet may be beneficial for patients with McArdle disease, based on improvements in either endurance or muscle energetics, as assessed by phosphorous MR spectroscopy. In healthy subjects, proteins contribute very little to energy metabolism during exercise, which questions the effect of protein in McArdle disease.. In a crossover, open design, we studied seven patients with McArdle disease, who were randomised to follow either a carbohydrate- or protein-rich diet for 3 days before testing. Calorific intake on each diet was identical, and was adjusted to the subject's weight, age and sex. After each diet, exercise tolerance and maximal work capacity were tested on a bicycle ergometer, using a constant workload for 15 minutes followed by an incremental workload to exhaustion.. During the constant workload, heart rate and perceived exertion were consistently lower (p<0.0005) on the carbohydrate- versus protein-rich diet. Patients also had a 25% improvement in maximal oxidative work capacity on the carbohydrate versus the protein diet.. This study shows that patients with McArdle disease can improve their maximal work capacity and exercise tolerance to submaximal workloads by maintaining a diet high in carbohydrate instead of protein. The carbohydrate diet not only improves tolerance to everyday activities, but will probably also help to prevent exercise-induced episodes of muscle injury in McArdle disease.

Topics: Adult; Carbohydrates; Cross-Over Studies; Energy Intake; Exercise; Exercise Test; Exercise Tolerance; Female; Glycogen; Glycogen Storage Disease Type V; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Proteins

Topics: Adipose Tissue; Animals; Exercise Test; Female; Glycogen; Glycogen Storage Disease Type V; Lipids; Male; Mice; Muscle, Skeletal; Oxidation-Reduction; Oxygen Consumption

Topics: Exercise; Glycogen; Glycogen Storage Disease Type V; Humans; Muscle, Skeletal; Muscles; Oxidation-Reduction

Glycogen storage disease type V (GSDV, McArdle disease) is a rare genetic myopathy caused by deficiency of the muscle isoform of glycogen phosphorylase (PYGM). This results in a block in the use of muscle glycogen as an energetic substrate, with subsequent exercise intolerance. The pathobiology of GSDV is still not fully understood, especially with regard to some features such as persistent muscle damage (i.e., even without prior exercise). We aimed at identifying potential muscle protein biomarkers of GSDV by analyzing the muscle proteome and the molecular networks associated with muscle dysfunction in these patients. Muscle biopsies from eight patients and eight healthy controls showing none of the features of McArdle disease, such as frequent contractures and persistent muscle damage, were studied by quantitative protein expression using isobaric tags for relative and absolute quantitation (iTRAQ) followed by artificial neuronal networks (ANNs) and topology analysis. Protein candidate validation was performed by Western blot. Several proteins predominantly involved in the process of muscle contraction and/or calcium homeostasis, such as myosin, sarcoplasmic/endoplasmic reticulum calcium ATPase 1, tropomyosin alpha-1 chain, troponin isoforms, and alpha-actinin-3, showed significantly lower expression levels in the muscle of GSDV patients. These proteins could be potential biomarkers of the persistent muscle damage in the absence of prior exertion reported in GSDV patients. Further studies are needed to elucidate the molecular mechanisms by which PYGM controls the expression of these proteins.

Topics: Biomarkers; Glycogen; Glycogen Storage Disease Type V; Humans; Muscle, Skeletal; Protein Isoforms; Proteome

McArdle disease is an autosomal recessive genetic disorder caused by a deficiency of the glycogen phosphorylase (myophosphorylase) enzyme, which muscles need to break down glycogen into glucose for energy. Symptoms include exercise intolerance, with fatigue, muscle pain, and cramps being manifested during the first few minutes of exercise, which may be accompanied by rhabdomyolysis.. This case report describes for the first time the clinical features, diagnosis and management of a 20 year-old patient with anorexia nervosa and McArdle disease, documented by means of muscle biopsy.. Anorexia nervosa and McArdle disease interact in a detrimental bidirectional way. In addition, some laboratory parameter alterations (e.g., elevated values of creatine kinase) commonly attributed to the specific features of eating disorders (e.g., excessive exercising) may delay the diagnosis of metabolic muscle diseases. On the other hand, the coexistence of a chronic disease, such as McArdle disease, whose management requires the adoption of a healthy lifestyle, can help to engage patients in actively addressing their eating disorder.

Topics: Adult; Anorexia Nervosa; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Muscle, Skeletal; Young Adult

McArdle's disease is caused by a mutation in the PYGM gene, causing a muscle myophosphorylase deficiency, altering the release of glucose-1-P from glycogen. It usually manifests itself in childhood with early and excessive tiredness, myalgias, cramps and contractures or rhabdomyolysis, although it is not usually diagnosed until adulthood. Creatine kinase increases sharply during exercise. Four pediatric patients are presented, the pathophysiology is summarized, and a diagnostic algorithm is proposed.. Ages between 6 and 14 years, the anamnesis, physical examination, biochemistry, elec-tro-myogram, ischemia test and genetic study are described. Muscle biopsy in a single patient. The algorithm was developed from the ischemia test.. In the three men, myalgias appeared after finishing each sports session. Phenomenon 'second wind' in one case. Ischemia test without lactate elevation and marked ammonia elevation in all. Only one muscle biopsy with glycogen deposits and absence of myophosphorylase. PYGM gene with homozygous mutations in all. Dietary treatment attenuated their symptoms during aerobic exercises.. The ischemia test was very useful to demonstrate a dysfunction in anaerobic glycolysis. It is worth noting that oral glucose supplementation is very useful in McArdle disease, but is contraindicated in all six defects of anaerobic glycolysis. The algorithm also allows targeting the defect of 20 metabolic or structural myopathies, which are summarized.. Enfermedad de McArdle en cuatro pacientes pediátricos. Algoritmo diagnóstico ante una intolerancia al ejercicio.. Introducción. La enfermedad de McArdle está causada por una mutación en el gen PYGM y déficit de miofosforilasa muscular, resultando alterada la liberación de glucosa-1-P a partir del glucógeno. Suele manifestarse en la infancia con cansancio precoz y excesivo, mialgias, calambres y contracturas o rabdomiólisis, aunque no suele diagnosticarse hasta la etapa adulta. La creatincinasa se incrementa durante el ejercicio. Se presentan cuatro pacientes pediátricos, se resume la fisiopatología y se propone un algoritmo diagnóstico. Pacientes y métodos. Pacientes con edades entre 6 y 14 años. Se describe la anamnesis, la exploración física, la bioquímica, el electromiograma, el test de isquemia y el estudio genético, con biopsia muscular a un solo paciente. Se elabora un algoritmo a partir del test de isquemia. Resultados. En los tres varones, las mialgias aparecieron tras finalizar cada sesión deportiva, con un fenómeno second wind en un caso. Se apreció un test de isquemia sin elevación del lactato y marcada elevación del amonio en todos, una biopsia muscular con depósitos de glucógeno y ausencia de miofosforilasa, y gen PYGM con mutaciones homocigotas en todos. El tratamiento dietético les atenuó la sintomatología durante los ejercicios aeróbicos. Conclusiones. El test de isquemia resultó muy útil para demostrar una disfunción en la glucólisis anaeróbica. Se destaca que el suplemento oral de glucosa es muy útil para la enfermedad de McArdle, pero está contraindicado en los seis defectos de la glucólisis anaeróbica. El algoritmo también permite orientar el defecto de 20 miopatías metabólicas o estructurales, que se resumen.

Topics: Adolescent; Adult; Algorithms; Child; Glucose; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Male

McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity.

Topics: Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Induced Pluripotent Stem Cells; Technology

McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO. In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses.

Topics: Animals; Exercise Tolerance; Female; Glycogen; Glycogen Storage Disease Type V; Male; Mice; Mitochondria; Muscle, Skeletal

McArdle's disease, known as blockage of muscle glycogen metabolism, is characterized by glycogen accumulation of chains in skeletal striated muscles. One of the typical symptoms of the disease is the feeling of intolerance to exercise. Severe muscle cram and contracture, which often cause stiffness, occur due to a lack of muscle energy substrate during the exercise. These factors can lead to muscle damage, myoglobinuria, and, in severe cases, renal failure and rhabdomyolysis. Rhabdomyolysis is a syndrome that presents injury and necrosis of muscle cells leading to the release of intracellular material to the circulatory system. The present study aimed to report rhabdomyolysis in an individual with McArdle's disease after exercise of walking with low intensity. Patient, aged 33 years, was treated in the emergency room of a hospital located in the State of Rio de Janeiro, Brazil. After performing a full lap on the block of home (~500 m in ~4 min 37 s), walking at a moderate speed (~6.5 km/h), the individual felt sick and was rescued, later being hospitalized. The examinations collected presented hematocrit (HCT) compatible with chronic disease anemia and myoglobinuria. The patient was discharged from the intensive care center on the 3

Topics: Brazil; Exercise; Glycogen; Glycogen Storage Disease Type V; Humans; Myoglobinuria; Rhabdomyolysis

McArdle disease is caused by recessive mutations in PYGM gene. The condition is considered to cause a "pure" muscle phenotype with symptoms including exercise intolerance, inability to perform isometric activities, contracture, and acute rhabdomyolysis leading to acute renal failure. This is a retrospective observational study aiming to describe phenotypic and genotypic features of a large cohort of patients with McArdle disease between 2011 and 2019. Data relating to genotype and phenotype, including frequency of rhabdomyolysis, fixed muscle weakness, gout and comorbidities, inclusive of retinal disease (pattern retinal dystrophy) and thyroid disease, were collected. Data from 197 patients are presented. Seven previously unpublished PYGM mutations are described. Exercise intolerance (100%) and episodic rhabdomyolysis (75.6%) were the most common symptoms. Fixed muscle weakness was present in 82 (41.6%) subjects. Unexpectedly, ptosis was observed in 28 patients (14.2%). Hyperuricaemia was a common finding present in 88 subjects (44.7%), complicated by gout in 25% of cases. Thyroid dysfunction was described in 30 subjects (15.2%), and in 3 cases, papillary thyroid cancer was observed. Pattern retinal dystrophy was detected in 15 out of the 41 subjects that underwent an ophthalmic assessment (36.6%). In addition to fixed muscle weakness, ptosis was a relatively common finding. Surprisingly, dysfunction of thyroid and retinal abnormalities were relatively frequent comorbidities. Further studies are needed to better clarify this association, although our finding may have important implication for patient management.

Topics: Adult; Female; Genotype; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Male; Middle Aged; Muscle Weakness; Muscle, Skeletal; Mutation; Phenotype; Retinal Dystrophies; Retrospective Studies; Rhabdomyolysis; Thyroid Diseases; United Kingdom

McArdle disease is a disorder of carbohydrate metabolism that causes painful skeletal muscle cramps and skeletal muscle damage leading to transient myoglobinuria and increased risk of kidney failure. McArdle disease is caused by recessive mutations in the muscle glycogen phosphorylase (PYGM) gene leading to absence of PYGM enzyme in skeletal muscle and preventing access to energy from muscle glycogen stores. There is currently no cure for McArdle disease. Using a preclinical animal model, we aimed to identify a clinically translatable and relevant therapy for McArdle disease. We evaluated the safety and efficacy of recombinant adeno-associated virus serotype 8 (rAAV8) to treat a murine model of McArdle disease via delivery of a functional copy of the disease-causing gene, Pygm. Intraperitoneal injection of rAAV8-Pygm at post-natal day 1-3 resulted in Pygm expression at 8 weeks of age, accompanied by improved skeletal muscle architecture, reduced accumulation of glycogen and restoration of voluntary running wheel activity to wild-type levels. We did not observe any adverse reaction to the treatment at 8 weeks post-injection. Thus, we have investigated a highly promising gene therapy for McArdle disease with a clear path to the ovine large animal model endemic to Western Australia and subsequently to patients.

Topics: Animals; Disease Models, Animal; Female; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Inflammation; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal

Muscle glycogen phosphorylase (PYGM) is a key enzyme in the first step of glycogenolysis. Mutation in the PYGM gene leads to autosomal recessive McArdle disease. Patients suffer from exercise intolerance with premature fatigue, muscle cramps and myalgia due to lack of available glucose in muscles. So far, no efficient treatment has been found. The zebrafish has many experimental advantages, and was successfully implemented as an animal model of human myopathies. Since zebrafish skeletal muscles share high similarity with human skeletal muscles, it is our animal of choice to investigate the impact of Pygm knockdown on skeletal muscle tissue. The two forms of the zebrafish enzyme, Pygma and Pygmb, share more than 80% amino acid sequence identity with human PYGM. We show that the Pygm level varies at both the mRNA and protein level in distinct stages of zebrafish development, which is correlated with glycogen level. The Pygm distribution in muscles varies from dispersed to highly organized at 72 hpf. The pygma and pygmb morpholino knockdown resulted in a reduced Pygm level in zebrafish morphants, which exhibited altered, disintegrated muscle structure and accumulation of glycogen granules in the subsarcolemmal region. Thus, lowering the Pygm level in zebrafish larvae leads to an elevated glycogen level and to morphological muscle changes mimicking the symptoms of human McArdle disease. The zebrafish model of this human disease might contribute to further understanding of its molecular mechanisms and to the development of appropriate treatment.

Topics: Animals; Disease Models, Animal; Gene Knockdown Techniques; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Muscle, Skeletal; Mutation; RNA, Messenger; Zebrafish

Brain and muscle glycogen are generally thought to function as local glucose reserves, for use during transient mismatches between glucose supply and demand. However, quantitative measures show that glucose supply is likely never rate-limiting for energy metabolism in either brain or muscle under physiological conditions. These tissues nevertheless do utilize glycogen during increased energy demand, despite the availability of free glucose, and despite the ATP cost of cycling glucose through glycogen polymer. This seemingly wasteful process can be explained by considering the effect of glycogenolysis on the amount of energy obtained from ATP (ΔG'

Topics: Adenosine Triphosphate; Animals; Astrocytes; Brain; Glycogen; Glycogen Phosphorylase; Glycogen Storage Disease Type V; Glycogenolysis; Humans; Muscle Cells; Muscle, Skeletal; Phosphates; Phosphocreatine; Thermodynamics

McArdle disease (glycogen storage disease type V) is an inborn error of skeletal muscle metabolism, which affects glycogen phosphorylase (myophosphorylase) activity leading to an inability to break down glycogen. Patients with McArdle disease are exercise intolerant, as muscle glycogen-derived glucose is unavailable during exercise. Metabolic adaptation to blocked muscle glycogenolysis occurs at rest in the McArdle mouse model, but only in highly glycolytic muscle. However, it is unknown what compensatory metabolic adaptations occur during exercise in McArdle disease.. In this study, 8-week old McArdle and wild-type mice were exercised on a treadmill until exhausted. Dissected muscles were compared with non-exercised, age-matched McArdle and wild-type mice for histology and activation and expression of proteins involved in glucose uptake and glycogenolysis.. Investigation of expression and activation of proteins involved in glycolytic flux revealed that in glycolytic, but not oxidative muscle from exercised McArdle mice, the glycolytic flux had changed compared to that in wild-type mice. Specifically, exercise triggered in glycolytic muscle a differentiated activation of insulin receptor, 5' adenosine monophosphate-activated protein kinase, Akt and hexokinase II expression, while inhibiting glycogen synthase, suggesting that the need and adapted ability to take up blood glucose and use it for metabolism or glycogen storage is different among the investigated muscles.. The main finding of the study is that McArdle mouse muscles appear to adapt to the energy crisis by increasing expression and activation of proteins involved in blood glucose metabolism in response to exercise in the same directional way across the investigated muscles.

Topics: Animals; Disease Models, Animal; Glycogen; Glycogen Storage Disease Type V; Humans; Mice; Muscle, Skeletal; Physical Conditioning, Animal

Although they are unable to utilize muscle glycogen, McArdle mice adapt favourably to an individualized moderate-intensity endurance exercise training regime. Yet, they fail to reach the performance capacity of healthy mice with normal glycogen availability. There is a remarkable difference in the protein networks involved in muscle tissue adaptations to endurance exercise training in mice with and without glycogen availability. Indeed, endurance exercise training promoted the expression of only three proteins common to both McArdle and wild-type mice: LIMCH1, PARP1 and TIGD4. In turn, trained McArdle mice presented strong expression of mitogen-activated protein kinase 12 (MAPK12).. McArdle's disease is an inborn disorder of skeletal muscle glycogen metabolism that results in blockade of glycogen breakdown due to mutations in the myophosphorylase gene. We recently developed a mouse model carrying the homozygous p.R50X common human mutation (McArdle mouse), facilitating the study of how glycogen availability affects muscle molecular adaptations to endurance exercise training. Using quantitative differential analysis by liquid chromatography with tandem mass spectrometry, we analysed the quadriceps muscle proteome of 16-week-old McArdle (n = 5) and wild-type (WT) (n = 4) mice previously subjected to 8 weeks' moderate-intensity treadmill training or to an equivalent control (no training) period. Protein networks enriched within the differentially expressed proteins with training in WT and McArdle mice were assessed by hypergeometric enrichment analysis. Whereas endurance exercise training improved the estimated maximal aerobic capacity of both WT and McArdle mice as compared with controls, it was ∼50% lower than normal in McArdle mice before and after training. We found a remarkable difference in the protein networks involved in muscle tissue adaptations induced by endurance exercise training with and without glycogen availability, and training induced the expression of only three proteins common to McArdle and WT mice: LIM and calponin homology domains-containing protein 1 (LIMCH1), poly (ADP-ribose) polymerase 1 (PARP1 - although the training effect was more marked in McArdle mice), and tigger transposable element derived 4 (TIGD4). Trained McArdle mice presented strong expression of mitogen-activated protein kinase 12 (MAPK12). Through an in-depth proteomic analysis, we provide mechanistic insight into how glycogen availability affects muscle protein signalling adaptations to endurance exercise training.

Topics: Animals; Disease Models, Animal; Exercise Tolerance; Glycogen; Glycogen Storage Disease Type V; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Muscle, Skeletal; Physical Conditioning, Animal; Protein Interaction Maps; Proteomics

McArdle disease and mitochondrial myopathy impair muscle oxidative phosphorylation (OXPHOS) by distinct mechanisms: the former by restricting oxidative substrate availability caused by blocked glycogen breakdown, the latter because of intrinsic respiratory chain defects. We applied metabolic profiling to systematically interrogate these disorders at rest, when muscle symptoms are typically minimal, and with exercise, when symptoms of premature fatigue and potential muscle injury are unmasked. At rest, patients with mitochondrial disease exhibit elevated lactate and reduced uridine; in McArdle disease purine nucleotide metabolites, including xanthine, hypoxanthine, and inosine are elevated. During exercise, glycolytic intermediates, TCA cycle intermediates, and pantothenate expand dramatically in both mitochondrial disease and control subjects. In contrast, in McArdle disease, these metabolites remain unchanged from rest; but urea cycle intermediates are increased, likely attributable to increased ammonia production as a result of exaggerated purine degradation. Our results establish skeletal muscle glycogen as the source of TCA cycle expansion that normally accompanies exercise and imply that impaired TCA cycle flux is a central mechanism of restricted oxidative capacity in this disorder. Finally, we report that resting levels of long-chain triacylglycerols in mitochondrial myopathy correlate with the severity of OXPHOS dysfunction, as indicated by the level of impaired O

Topics: Adolescent; Adult; Aged; Citric Acid Cycle; Electron Transport; Energy Metabolism; Exercise; Female; Glycogen; Glycogen Storage Disease Type V; Heart Rate; Humans; Male; Metabolome; Middle Aged; Mitochondria; Mitochondrial Myopathies; Muscle, Skeletal; Oxidative Phosphorylation; Oxygen Consumption; Triglycerides; Young Adult

We investigated metabolism and physiological responses to exercise in an 18-year-old woman with multiple congenital abnormalities and exertional muscle fatigue, tightness, and rhabdomyolysis.. We studied biochemistry in muscle and fibroblasts, performed mutation analysis, assessed physiological responses to forearm and cycle-ergometer exercise combined with stable-isotope techniques and indirect calorimetry, and evaluated the effect of IV glucose infusion and oral sucrose ingestion on the exercise response.. Phosphoglucomutase type 1 (PGM1) activity in muscle and fibroblasts was severely deficient and PGM1 in muscle was undetectable by Western blot. The patient was compound heterozygous for missense (R422W) and nonsense (Q530X) mutations in PGM1. Forearm exercise elicited no increase in lactate, but an exaggerated increase in ammonia, and provoked a forearm contracture. Comparable to patients with McArdle disease, the patient developed a 'second wind' with a spontaneous fall in exercise heart rate and perceived exertion. Like in McArdle disease, this was attributable to an increase in muscle oxidative capacity. Carbohydrate oxidation was blocked during exercise, and the patient had exaggerated oxidation of fat to fuel exercise. Exercise heart rate and perceived exertion were lower after IV glucose and oral sucrose. Muscle glycogen level was low normal.. The second wind phenomenon has been considered to be pathognomonic for McArdle disease, but we demonstrate that it can also be present in PGM1 deficiency. We show that severe loss of PGM1 activity causes blocked muscle glycogenolysis that mimics McArdle disease, but may also limit glycogen synthesis, which broadens the phenotypic spectrum of this disorder.

Topics: Adolescent; Biopsy; Exercise; Female; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Glycogenolysis; Heart Rate; Humans; Lactates; Male; Muscle Fatigue; Muscle, Skeletal; Muscular Diseases; Oxidation-Reduction; Oxygen Consumption; Physical Exertion; Rhabdomyolysis; Skin

McArdle disease, also termed 'glycogen storage disease type V', is a disorder of skeletal muscle carbohydrate metabolism caused by inherited deficiency of the muscle-specific isoform of glycogen phosphorylase (GP-MM). It is an autosomic recessive disorder that is caused by mutations in the PYGM gene and typically presents with exercise intolerance, i.e. episodes of early exertional fatigue frequently accompanied by rhabdomyolysis and myoglobinuria. Muscle biopsies from affected individuals contain subsarcolemmal deposits of glycogen. Besides GP-MM, two other GP isoforms have been described: the liver (GP-LL) and brain (GP-BB) isoforms, which are encoded by the PYGL and PYGB genes, respectively; GP-BB is the main GP isoform found in human and rat foetal tissues, including the muscle, although its postnatal expression is dramatically reduced in the vast majority of differentiated tissues with the exception of brain and heart, where it remains as the major isoform. We developed a cell culture model from knock-in McArdle mice that mimics the glycogen accumulation and GP-MM deficiency observed in skeletal muscle from individuals with McArdle disease. We treated mouse primary skeletal muscle cultures in vitro with sodium valproate (VPA), a histone deacetylase inhibitor. After VPA treatment, myotubes expressed GP-BB and a dose-dependent decrease in glycogen accumulation was also observed. Thus, this in vitro model could be useful for high-throughput screening of new drugs to treat this disease. The immortalization of these primary skeletal muscle cultures could provide a never-ending source of cells for this experimental model. Furthermore, VPA could be considered as a gene-expression modulator, allowing compensatory expression of GP-BB and decreased glycogen accumulation in skeletal muscle of individuals with McArdle disease.

Topics: Animals; Brain; Cells, Cultured; Glycogen; Glycogen Phosphorylase; Glycogen Storage Disease Type V; Homozygote; Humans; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; Protein Isoforms; Valproic Acid

This is the first study to analyse the effect of muscle glycogen phosphorylase depletion in metabolically different muscle types. In McArdle mice, muscle glycogen phosphorylase is absent in both oxidative and glycolytic muscles. In McArdle mice, the glycogen debranching enzyme (catabolic) is increased in oxidative muscles, whereas the glycogen branching enzyme (anabolic) is increased in glycolytic muscles. In McArdle mice, total glycogen synthase is decreased in both oxidative and glycolytic muscles, whereas the phosphorylated inactive form of the enzyme is increased in both oxidative and glycolytic enzymes. In McArdle mice, glycogen content is higher in glycolytic muscles than in oxidative muscles. Additionally, in all muscles analysed, the glycogen content is higher in males than in females. The maximal endurance capacity of the McArdle mice is significantly lower compared to heterozygous and wild-type mice.. McArdle disease, caused by inherited deficiency of the enzyme muscle glycogen phosphorylase (GP-MM), is arguably the paradigm of exercise intolerance. The recent knock-in (p.R50X/p.R50X) mouse disease model allows an investigation of the phenotypic consequences of muscle glycogen unavailability and the physiopathology of exercise intolerance. We analysed, in 2-month-old mice [wild-type (wt/wt), heterozygous (p.R50X/wt) and p.R50X/p.R50X)], maximal endurance exercise capacity and the molecular consequences of an absence of GP-MM in the main glycogen metabolism regulatory enzymes: glycogen synthase, glycogen branching enzyme and glycogen debranching enzyme, as well as glycogen content in slow-twitch (soleus), intermediate (gastrocnemius) and glycolytic/fast-twitch (extensor digitorum longus; EDL) muscles. Compared with wt/wt, exercise capacity (measured in a treadmill test) was impaired in p.R50X/p.R50X (∼48%) and p.R50X/wt mice (∼18%). p.R50X/p.R50X mice showed an absence of GP-MM in the three muscles. GP-MM was reduced in p.R50X/wt mice, especially in the soleus, suggesting that the function of 'slow-twitch' muscles is less dependent on glycogen catabolism. p.R50X/p.R50X mice showed increased glycogen debranching enzyme in the soleus, increased glycogen branching enzyme in the gastrocnemius and EDL, as well as reduced levels of mucle glycogen synthase protein in the three muscles (mean ∼70%), reflecting a protective mechanism for preventing deleterious glycogen accumulation. Additionally, glycogen content was highest in the EDL of p.R50X/p.R50X mice. Amongst other findings, the present study shows that the expression of the main muscle glycogen regulatory enzymes differs depending on the muscle phenotype (slow- vs. fast-twitch) and that even partial GP-MM deficiency affects maximal endurance capacity. Our knock-in model might help to provide insights into the importance of glycogen on muscle function.

Topics: Animals; Disease Models, Animal; Female; Glycogen; Glycogen Phosphorylase; Glycogen Storage Disease Type V; Male; Mice, Transgenic; Muscle, Skeletal; Phenotype; Physical Conditioning, Animal; Protein Isoforms; RNA, Messenger

Topics: Genotype; Glycogen; Glycogen Storage Disease Type V; Humans; Phenotype

Topics: Brain; Glycogen; Glycogen Storage Disease Type V; Humans; Muscle, Skeletal; Muscular Diseases

Creatine kinase (CK) and myoglobin (Mb) do not possess all good qualities as biomarkers of skeletal muscle damage. We investigated the utility of troponin I (TnI) and telethonin (Tcap) as markers and examined their temporal profiles after skeletal muscle damage.. Plasma profiles were measured before and after exercise in 3 groups: subjects affected by either Becker muscular dystrophy or McArdle disease, and healthy subjects.. Mb and TnI appeared early in the blood, and the increase of TnI was only observed in patients with muscle disease. The CK increase was more delayed in plasma. Tcap was not detectable at any time.. Our results suggest that TnI is a marker of more severe damage signifying sarcomeric damage, and it could therefore be an important supplement to CK and Mb in clinical practice. Tcap is not useful as a marker for skeletal muscle damage.

Topics: Adolescent; Adult; Biomarkers; Case-Control Studies; Connectin; Creatine Kinase; Energy Metabolism; Exercise; Female; Glycogen; Glycogen Storage Disease Type V; Humans; Male; Middle Aged; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Pilot Projects; Sarcomeres; Troponin I; Young Adult

McArdle disease is caused by a deficiency of myophosphorylase and currently a satisfactory treatment is not available. The injection of notexin into, or the layering of notexin onto, the muscles of affected sheep resulted in necrosis followed by regeneration of muscle fibres with the expression of both non-muscle isoforms of phosphorylase within the fibres and a reduction of the amount of glycogen in the muscle with an increase in the strength of contraction and a decrease in fatiguability in the muscle fibres. The sustained re-expression of both the brain and liver isoforms of phosphorylase within the muscle fibres provides further emphasis that strategies to enhance the re-expression of these isoforms should be investigated as a possible treatment for McArdle disease.

Topics: Animals; Blotting, Western; Elapid Venoms; Glycogen; Glycogen Phosphorylase; Glycogen Storage Disease Type V; Isoenzymes; Male; Muscle Fatigue; Muscle Strength; Muscle, Skeletal; Necrosis; Neurotoxins; Phosphorylases; Regeneration; Sheep; Time Factors

To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD).. Patient 1 (39 years old) had mild exercise-induced forearm pain, and EMG showed a myopathic pattern. Patient 2 (69 years old) had raised levels of creatine kinase (CK) for more than 6 months after statin treatment. Both patients had increased glycogen levels in muscle and PHK activity <11% of normal. Two novel pathogenic nonsense mutations were found in the PHKA1 gene. The metabolic response to anaerobic forearm exercise and aerobic cycle exercise was studied in the patients and 5 healthy subjects.. Ischemic exercise showed a normal 5-fold increase in plasma lactate (peak 5.7 and 6.9 mmol/L) but an exaggerated 5-fold increase in ammonia (peak 197 and 171 μmol/L; control peak range 60-113 μmol/L). An incremental exercise test to exhaustion revealed a blunted lactate response (5.4 and 4.8 mmol/L) vs that for control subjects (9.6 mmol/L; range 7.1-14.3 mmol/L). Fat and carbohydrate oxidation rates at 70% of peak oxygen consumption were normal. None of the patients developed a second wind phenomenon or improved their work capacity with an IV glucose infusion.. Our findings demonstrate that muscle PHK deficiency may present as an almost asymptomatic condition, despite a mild impairment of muscle glycogenolysis, raised CK levels, and glycogen accumulation in muscle. The relative preservation of glycogenolysis is probably explained by an alternative activation of myophosphorylase by AMP and P(i) at high exercise intensities.

Topics: Adult; Aged; Ammonia; Biopsy; Carbohydrate Metabolism; Creatine Kinase; Exercise; Exercise Test; Forearm; Genetic Variation; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Glycogenolysis; Humans; Ischemia; Lactates; Lipid Metabolism; Male; Muscle, Skeletal; Oxygen Consumption; Pain; Phenotype; Phosphorylase Kinase; Regional Blood Flow

McArdle disease (glycogenosis type V), the most common muscle glycogenosis, is a recessive disorder caused by mutations in PYGM, the gene encoding myophosphorylase. Patients with McArdle disease typically experience exercise intolerance manifested as acute crises of early fatigue and contractures, sometimes with rhabdomyolysis and myoblobinuria, triggered by static muscle contractions or dynamic exercises. Currently, there are no therapies to restore myophosphorylase activity in patients. Although two spontaneous animal models for McArdle disease have been identified (cattle and sheep), they have rendered a limited amount of information on the pathophysiology of the disorder; therefore, there have been few opportunities for experimental research in the field. We have developed a knock-in mouse model by replacing the wild-type allele of Pygm with a modified allele carrying the common human mutation, p.R50X, which is the most frequent cause of McArdle disease. Histochemical, biochemical and molecular analyses of the phenotype, as well as exercise tests, were carried out in homozygotes, carriers and wild-type mice. p.R50X/p.R50X mice showed undetectable myophosphorylase protein and activity in skeletal muscle. Histochemical and biochemical analyses revealed massive muscle glycogen accumulation in homozygotes, in contrast to heterozygotes or wild-type mice, which did not show glycogen accumulation in this tissue. Additional characterization confirmed a McArdle disease-like phenotype in p.R50X/p.R50X mice, i.e. they had hyperCKaemia and very poor exercise performance, as assessed in the wire grip and treadmill tests (6% and 5% of the wild-type values, respectively). This model represents a powerful tool for in-depth studies of the pathophysiology of McArdle disease and other neuromuscular disorders, and for exploring new therapeutic approaches for genetic disorders caused by premature stop codon mutations.

Topics: Alleles; Animals; Creatine Kinase; Disease Models, Animal; Female; Gene Knock-In Techniques; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Heterozygote; Homozygote; Male; Mice; Muscle, Skeletal; Myoglobin; Myoglobinuria; Physical Conditioning, Animal

There is individual variability in the clinical manifestation of McArdle disease, with women generally being more severely affected than men. We compared clinical presentation and exercise capacity between (i) four women with McArdle disease (aged 17, 36, 42 and 70 years) who were also carriers of the K153R variant in the myostatin (GDF-8) gene and in (ii) four women with this disorder matched forage (16, 33, 40 and 69 years), lifestyle, and documented genotype modulators of this disease (ACE, AMPD1 and ACTN3), who did not carry the myostatin variant. Except in the youngest patient, clinical severity was higher in K153R carriers than in their K/K(2) controls (aged 33, 40 and 46 years). Peak cardiorespiratory capacity was very low (< or = 13 mLO(2)/kg/min) in all K153R carriers.

Topics: Actinin; Adolescent; Adult; Aged; AMP Deaminase; DNA Mutational Analysis; Exercise Tolerance; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glycogen; Glycogen Storage Disease Type V; Heterozygote; Humans; Muscle Weakness; Muscle, Skeletal; Mutation; Myostatin; Peptidyl-Dipeptidase A; Phenotype; Respiratory Insufficiency

McArdle's disease (MAD) is a rare hereditary myopathy secondary to a deficit in myophosphorylase, an essential enzyme for the use of muscular glycogen reserves. Exercise intolerance to a variable degree is the fundamental manifestation. Muscular enzymes are usually normal or slightly elevated, except during episodes of rhabdomyolysis. Generally, the electromyogram has poor sensitivity for the diagnosis of exercise myopathies. The muscular biopsy can be misleadingly normal. The role of MRI in the diagnosis of MAD is not well clarified in the literature. We report the case of a 16-year-old patient, hospitalized in July 2008 for exercise intolerance. On admission, he was asymptomatic and the physical examination was non contributive. Serum creatine kinase levels and renal function measures were normal. Cycloergometer exercise testing unmasked the disease. EMG and muscular biopsies were normal. During the second hospitalization, this time for rhabdomyolysis, T2 weighted MRI of the thighs showed high intensity signals from the gracilis muscles. The control MRI, made after 2 weeks of rest, was normal. Right gracilis muscle biopsy demonstrated excess glycogen with myophosphorylase deficiency, establishing the diagnosis of MAD. MAD is a rare metabolic myopathy to consider in patients with a history of exercise intolerance. The muscle biopsy can be misleadingly normal and should be, to our opinion, be guided by MRI findings.

Topics: Adolescent; Biopsy; Electromyography; Exercise; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Magnetic Resonance Imaging; Male; Muscle, Skeletal; Rhabdomyolysis

It is unclear to what extent muscle phosphorylase b kinase (PHK) deficiency is associated with exercise-related symptoms and impaired muscle metabolism, because 1) only four patients have been characterized at the molecular level, 2) reported symptoms have been nonspecific, and 3) lactate responses to ischemic handgrip exercise have been normal.. We studied a 50-year-old man with X-linked PHK deficiency using ischemic forearm and cycle ergometry exercise tests to define the derangement of muscle metabolism. We compared our findings with those in patients with McArdle disease and in healthy subjects.. Sequencing of PHKA1 showed a novel pathogenic mutation (c.831G>A) in exon 7. There was a normal increase of plasma lactate during forearm ischemic exercise, but lactate did not change during dynamic, submaximal exercise in contrast to the fourfold increase in healthy subjects. Constant workload elicited a second wind in all patients with McArdle disease, but not in the patient with PHK deficiency. IV glucose administration appeared to improve exercise tolerance in the patient with PHK deficiency, but not to the same extent as in the patients with McArdle disease. Lipolysis was higher in the patient with PHK deficiency than in controls.. These findings demonstrate that X-linked PHK deficiency causes a mild metabolic myopathy with blunted muscle glycogen breakdown and impaired lactate production during dynamic exercise, which impairs oxidative capacity only marginally. The different response of lactate to submaximal and maximal exercise is likely related to differential activation mechanisms for myophosphorylase.

Topics: Chromosomes, Human, X; Exercise Test; Glycogen; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VIII; Glycogenolysis; Humans; Lactic Acid; Male; Middle Aged; Muscle Weakness; Muscle, Skeletal; Oxidative Stress; Phosphorylase Kinase; Physical Exertion; Point Mutation; Protein Subunits

Topics: Glycogen; Glycogen Storage Disease Type V; Humans; Muscle, Skeletal; Phosphorylase Kinase

Topics: Animals; Energy Metabolism; Glycogen; Glycogen Storage Disease Type V; Humans; Lactates; Lactic Acid; Mitochondrial Myopathies; Muscle Contraction; Muscle Fatigue; Muscle Fibers, Skeletal; Muscle, Skeletal; Sympathetic Nervous System

A 14-month-old girl was hospitalized due to repeated hyper-creatine kinase (CK)-emia during pyrexia. Mild hypotonia was observed, but other physical and neurological findings were unremarkable. The serum CK level was normal at rest or normothermia. Open muscle biopsy was performed on the rectus femoris, and showed glycogen storage and complete lack of phosphorylase activity histochemically and biochemically, establishing the diagnosis of McArdle disease. The diagnosis of McArdle disease in early infancy is uncommon. Until this study there have been no reports of clinical symptoms or muscle biopsy findings for McArdle disease in early childhood. This disease must be considered when transient hyper-CKemia is observed in infants, even if glycogen storage is unremarkable as compared with adult cases.

Topics: Biopsy; Creatine Kinase; Female; Fever; Glycogen; Glycogen Phosphorylase; Glycogen Storage Disease Type V; Humans; Immunohistochemistry; Infant; Microscopy, Electron; Muscle, Skeletal

We report on a Spanish family with myophosphorylase (EC 2.4.1.1) deficiency (McArdle's disease). The proband and his symptomatic sister were compound heterozygous for two novel mutations: a T-to-G transversion in exon 14 (c1722 T>G) that changes a tyrosine to a stop codon (Y573X), and a G-to-A transition in exon 15 (c1827 G>A) that disrupts the consensus signal at the donor splicing site. These findings further expand knowledge of the genetic bases of muscle glycogen phosphorylase deficiency.

Topics: Adult; Aged; Alternative Splicing; Child; Codon, Nonsense; Codon, Terminator; DNA Mutational Analysis; Exons; Female; Genetic Testing; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Male; Muscle, Skeletal; Mutation; Pedigree; RNA Splice Sites

Topics: Exercise Tolerance; Glycogen; Glycogen Storage Disease Type V; Glycolysis; Humans; Sucrose

Insulin action is decreased by high muscle glycogen concentrations in skeletal muscle. Patients with McArdle's disease have chronic high muscle glycogen levels and might therefore be at risk of developing insulin resistance. In this study, six patients with McArdle's disease and six matched control subjects were subjected to an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp. The muscle glycogen concentration was 103 +/- 45% higher in McArdle patients than in controls. Four of six McArdle patients, but none of the controls, had impaired glucose tolerance. The insulin-stimulated glucose utilization and the insulin-stimulated increase in glycogen synthase activity during the clamp were significantly lower in the patients than in controls (51.3 +/- 6.0 vs. 72.6 +/- 13.1 micromol x min(-1) x kg lean body mass(-1), P < 0.05, and 53 +/- 15 vs. 79 +/- 9%, P < 0.05, n = 6, respectively). The difference in insulin-stimulated glycogen synthase activity between the pairs was significantly correlated (r = 0.96, P < 0.002) with the difference in muscle glycogen level. The insulin-stimulated increase in Akt phosphorylation was smaller in the McArdle patients than in controls (45 +/- 13 vs. 76 +/- 13%, P < 0.05, respectively), whereas basal and insulin-stimulated glycogen synthase kinase 3alpha and protein phosphatase-1 activities were similar in the two groups. Furthermore, the ability of insulin to decrease and increase fat and carbohydrate oxidation, respectively, was blunted in the patients. In conclusion, these data show that patients with McArdle's glycogen storage disease are insulin resistant in terms of glucose uptake, glycogen synthase activation, and alterations in fuel oxidation. The data further suggest that skeletal muscle glycogen levels play an important role in the regulation of insulin-stimulated glycogen synthase activity.

Topics: Adult; Blood Glucose; Calcium-Calmodulin-Dependent Protein Kinases; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Glycogen; Glycogen Phosphorylase; Glycogen Storage Disease Type V; Glycogen Synthase; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Humans; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Oxidation-Reduction; Phosphoprotein Phosphatases; Phosphorylation; Protein Phosphatase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt

It has been suggested that 5'AMP-activated protein kinase (AMPK) is involved in the regulation of glucose and glycogen metabolism in skeletal muscle. We used patients with chronic high muscle glycogen stores and deficient glycogenolysis (McArdle's disease) as a model to address this issue. Six McArdle patients were compared with control subjects during exercise. Muscle alpha2AMPK activity increased in McArdle patients (from 1.3 +/- 0.2 to 1.9 +/- 0.2 pmol min(-1) mg(-1), P = 0.05) but not in control subjects (from 1.0 +/- 0.1 to 1.3 +/- 0.3 pmol min(-1) mg(-1)). Exercise-induced phosphorylation of the in vivo AMPK substrate acetyl CoA carboxylase (ACCbeta; Ser(221)) was higher (P < 0.01) in McArdle patients than in control subjects (18 +/- 3 vs. 10 +/- 1 arbitrary units). Exercise-induced whole-body glucose utilization was also higher in McArdle patients than in control subjects (P < 0.05). No correlation between individual AMPK or ACCbeta values and glucose utilization was observed. Glycogen synthase (GS) activity was decreased in McArdle patients from 11 +/- 1.3 to 5 +/- 1.2 % (P < 0.05) and increased in control subjects from 19 +/- 1.6 to 23 +/- 2.3 % (P < 0.05) in response to exercise. This was not associated with activity changes of GS kinase 3 or protein phosphatase 1, but the changes in GS activity could be due to changes in activity of AMPK or protein kinase A (PKA) as a negative correlation between either ACCbeta phosphorylation (Ser(221)) or plasma adrenaline and GS activity was observed. These findings suggest that GS activity is increased by glycogen breakdown and decreased by AMPK and possibly PKA activation and that the resultant GS activity depends on the relative strengths of the various stimuli. Furthermore, AMPK may be involved in the regulation of glucose utilization during exercise in humans, although the lack of correlation between individual AMPK activity or ACCbeta phosphorylation (Ser(221)) values and individual glucose utilization during exercise implies that AMPK may not be an essential regulator.

Topics: Acetyl-CoA Carboxylase; Adult; AMP-Activated Protein Kinases; Blood Glucose; Exercise; Female; Glucose; Glucose Transporter Type 4; Glycogen; Glycogen Storage Disease Type V; Glycogen Synthase; Hemodynamics; Hormones; Humans; Lactic Acid; Male; Monosaccharide Transport Proteins; Multienzyme Complexes; Muscle Proteins; Muscle, Skeletal; Phosphocreatine; Phosphoprotein Phosphatases; Phosphorylation; Protein Phosphatase 1; Protein Serine-Threonine Kinases; Respiratory Mechanics; Signal Transduction

We studied a 57-year-old female patient with clinical and biochemical evidences of McArdle's disease. Her muscle biopsy also revealed signs of mitochondrial proliferation, scattered RRF, and a deficit in complex I of the respiratory chain. Molecular genetic analysis showed that the patient was heterozygous for the most common mutation at codon 49 in the myophosphorylase gene. Mitochondrial DNA analysis of muscle tissue revealed an additional G-to-A transition at nucleotide position 7444 in the cytochrome c oxidase subunit I (COI) gene.

Topics: Codon; DNA Mutational Analysis; DNA, Mitochondrial; Electron Transport Complex I; Electron Transport Complex IV; Energy Metabolism; Exons; Female; Glycogen; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Middle Aged; Mitochondria, Muscle; Muscle Fibers, Skeletal; Muscle, Skeletal; NADH, NADPH Oxidoreductases; Point Mutation

Topics: Adult; Brain; Brain Diseases, Metabolic; Glycogen; Glycogen Storage Disease Type V; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Neurologic Examination

We studied a group of 14 patients from Northern Italy with myophosphorylase deficiency. The disease presented considerable clinical and biochemical heterogeneity, which was reflected at the molecular level. The clinical presentation was typical in 3 patients, mild in 7 (exercise intolerance), and severe in 4 (fixed weakness). Enzyme activity was undetectable in 10 patients, below 3% of control in 3, and 13% of control in one. Enzymatic protein was detectable immunologically only in 1 patient. Myophosphorylase mRNA was present in 8 patients, but in 7 of them it was reduced in amount. Two patients were homozygous for the common nonsense R49X mutation, 5 were heterozygous. Two missense mutations not previously observed were identified in this group of patients. The frequency of alleles with the R49X mutation was significantly lower in this group of patients than in previously reported series. Myophosphorylase deficiency is genetically heterogeneous even among patients living in a small region and with a common ethnic background.

Topics: Adolescent; Adult; Aged; Biopsy; Blotting, Northern; Child; Female; Glycogen; Glycogen Storage Disease Type V; Humans; Immunoblotting; Immunohistochemistry; Italy; Male; Middle Aged; Muscle, Skeletal; Mutation; Phosphorylases; Point Mutation; Polymerase Chain Reaction; RNA, Messenger

The feasibility of using adenovirus as a vector for the introduction of glycogen phosphorylase activity into myocytes has been examined. We used the C2C12 myoblast cell line to assay the impact of phosphorylase gene transfer on myocyte glycogen metabolism and to reproduce in vitro the two strategies proposed for the treatment of muscle genetic diseases, myoblast transplantation and direct DNA delivery. In this study, a recombinant adenovirus containing the muscle glycogen phosphorylase cDNA transcribed from the cytomegalovirus promoter (AdCMV-MGP) was used to transduce both differentiating myoblasts and nondividing mature myotube cells. Muscle glycogen phosphorylase mRNA levels and total phosphorylase activity were increased in both cell types after viral treatment although more efficiently in the differentiated myotubes. The increase in phosphorylase activity was transient (15 days) in myoblasts whereas in myotubes higher levels of phosphorylase gene expression and activity were reached, which remained above control levels for the duration of the study (20 days). The introduction of muscle phosphorylase into myotubes enhanced their glycogenolytic capacity. AdCMV MGP-transduced myotubes had lower glycogen levels under basal conditions. In addition, these engineered cells showed more extensive glycogenolysis in response to both adrenaline, which stimulates glycogen phosphorylase phosphorylation, and carbonyl cyanide m-chlorophenylhydrazone, a metabolic uncoupler. In conclusion, transfer of the muscle glycogen phosphorylase cDNA into myotubes confers an enhanced and regulatable glycogenolytic capacity. Thus this system might be useful for delivery of muscle glycogen phosphorylase and restoration of glycogenolysis in muscle cells from patients with muscle phosphorylase deficiency (McArdle's disease).

Topics: Adenoviridae; Cell Differentiation; Cells, Cultured; DNA, Complementary; Gene Transfer Techniques; Genetic Vectors; Glycogen; Glycogen Storage Disease Type V; Humans; Muscles; Phosphorylases

Topics: Adult; Glycogen; Glycogen Storage Disease Type V; Glycolysis; Humans; Male; Muscles; Pedigree

We report a family with McArdle's disease with several affected individuals in two generations. This unusual pedigree for an autosomal recessive disease is explained by the existence of manifesting heterozygotes in the maternal line. The presence of symptoms in heterozygotes seems to be due to a decrease in myophosphorylase activity below a critical threshold, ranging between 30% and 45% of normal mean value. The occurrence of several manifesting heterozygotes in the maternal line only can be explained by compound heterozygosity of a defective allele and a pseudodeficient allele for myophosphorylase, or by a genetic factor which regulates the phenotypic expression of the gene.

Topics: Adolescent; Adult; Densitometry; Electrophoresis, Polyacrylamide Gel; Female; Glycogen; Glycogen Storage Disease Type V; Heterozygote; Humans; Italy; Male; Muscles; Muscular Diseases; Pain; Phenotype; Phosphorylase a

Muscular glycogenosis is a disease resulting from genetical abnormalities altering an enzyme which is involved in glycogen metabolism. In addition to disorders of glycogenosis and glycolysis, there are other pathological processes such as alpha-glycosidase deficiency and diseases associated with abnormal polysaccharide structure. A short review of the various diseases with their particular features is reported.

Topics: Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type IV; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VII; Glycolysis; Humans; Muscles; Muscular Diseases

Glycogen storage disease was suspected in a 10-month-old boy. Initial technical problems did not permit the determination of the precise enzyme, deficiency, and type VI glycogen storage disease was only diagnosed at the age of 2 years. In the mean time, natural abundance 13C nuclear magnetic resonance evaluation of muscular and hepatic glycogen content indicated normal muscular glycogen and increased hepatic glycogen in our patient, a finding which strongly argued for the diagnosis of type VI glycogen storage disease. Even though the use of nuclear magnetic resonance might seem, in this situation, a somewhat circuitous means of reaching the diagnosis, it appears that nuclear magnetic resonance could provide a useful tool for a non-invasive diagnosis of glycogen storage diseases.

Topics: Creatine; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Humans; Infant; Liver Glycogen; Magnetic Resonance Spectroscopy; Male; Muscles

Topics: Animals; Glycogen; Glycogen Storage Disease Type V; Humans; Hydrolysis; Magnetic Resonance Imaging; Muscles; Physical Exertion; Rabbits; Regional Blood Flow

Hormonal, metabolic, and cardiovascular responses to 21 min of cycling in three saline- or glucose-infused men with McArdle's disease were compared with those of matched controls to elucidate whether mobilization of extramuscular fuel is enhanced to compensate for the lack of intramuscular glycogenolysis in patients with McArdle's disease. During exercise, all saline-infused patients compared with controls working at both the same absolute and at similar relative work rates had higher glucose production (31 +/- 7 vs. 19 +/- 5 and 26 +/- 4 mumol.min-1.kg-1) and utilization (34 +/- 8 vs. 22 +/- 2 and 28 +/- 4 mumol.min-1.kg-1); higher plasma glycerol (155 +/- 19 vs. 75 +/- 20 and 90 +/- 22 mumol/l), free fatty acids (487 +/- 175 vs. 295 +/- 47 and 202 +/- 52 mumol/l), growth hormone (7.7 +/- 2.8 vs. 2.6 +/- 1.1 and 3.6 +/- 3.4 mU/l), and cortisol (530 +/- 168 vs. 268 +/- 8 and 367 +/- 80 nmol/l), greater decrease in insulin (delta 57 +/- 4 vs. delta 11 +/- 8 and delta 11 +/- 23 pmol/l), and similar glucose concentrations. Furthermore, norepinephrine, epinephrine, and adrenocorticotropic hormone levels were higher and heart rate and cardiac output were higher during exercise in all patients than in controls at the same absolute work rate. Glucose infusion induced hyperglycemia and hyperinsulinemia in patients and inhibited the exercise-induced increases in glucose production, glycerol, free fatty acids, catecholamines, growth hormone, cortisol, and heart rate. In conclusion, feedback from metabolism in contracting muscle enhances hormonal responses and extramuscular substrate mobilization during exercise in McArdle's disease.

Topics: Adult; Energy Metabolism; Exercise; Glycogen; Glycogen Storage Disease Type V; Hemodynamics; Hormones; Humans; Lactates; Lactic Acid; Male; Muscles; Oxygen Consumption

To assess the role of glycogenolysis in mediating exercise-induced increases in muscle water as monitored by changes in muscle proton relaxation times on magnetic resonance imaging (MRI) and cross-sectional area (CSA), five patients with myophosphorylase deficiency (MPD) were compared with seven controls. Absolute and relative work loads were matched during ischemic handgrip and graded cycling, respectively. Relaxation times of active muscle did not increase after handgrip in MPD (T1: 1 +/- 14%, P greater than 0.1; T2: 4 +/- 4%, P greater than 0.1) but did in controls (T1: 59 +/- 30%, P less than 0.005; T2: 26 +/- 9%, P less than 0.005). The volume of exercised muscles, estimated by CSA, increased in both groups after handgrip (controls: 13.8 +/- 3.5%, n = 7, P less than 0.0001; MPD: 7.5 +/- 1.5%, n = 4, P less than 0.005), but the change was greater in controls (P less than 0.02). Ischemic handgrip in controls resulted in a large increase in finger flexor signal intensity (SI) on short tau-inversion recovery images (25 +/- 7%, n = 3; P less than 0.005 compared with preexercise) and a further increase with subsequent reflow (43 +/- 11%, n = 3; P less than 0.001 compared with rest); in MPD, SI did not increase. The ratio of active to inactive muscle SI did not increase from rest to maximal cycle exercise in MPD (0 +/- 20%, n = 2, P greater than 0.1) but did in normals (73 +/- 36%, n = 3; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Body Water; Exercise; Female; Glycogen; Glycogen Storage Disease Type V; Hand; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Muscles

Contrary to the accepted feedback control mechanism of glycogen biosynthesis in skeletal muscle, evidence is presented here leading to the conclusion that glycogen does not control the activity of glycogen synthase phosphatase in intact human skeletal muscle tissue.

Topics: Feedback; Glycogen; Glycogen Storage Disease Type V; Glycogen-Synthase-D Phosphatase; Humans; Muscles

Natural abundance 13C NMR (nuclear magnetic resonance) spectroscopy was used to distinguish patients suffering from muscle glycogenosis type V (McArdle's disease) from normal subjects by measuring their muscle glycogen content at rest. Proton-decoupled 13C spectra were obtained in 10-15 min from calf muscles at rest. The ratio of the glycogen/creatine signal areas was 12.9 +/- 1.7 in four McArdle's disease patients and 2.0 +/- 0.7 in seven normal subjects. This technique thus allows the non-invasive diagnosis of muscle glycogenosis.

Topics: Adult; Creatine; Glycogen; Glycogen Storage Disease Type V; Humans; Magnetic Resonance Spectroscopy; Middle Aged; Muscles

The level of glucose-1, 6-bisphosphate, a potent allosteric activator of phosphofructokinase, was markedly decreased in muscles of patients with glycogenosis type VII (muscle phosphofructokinase deficiency) and type V (muscle phosphorylase deficiency). Glucose-1-phosphate kinase activity in muscle was virtually absent in a patient with glycogenosis type VII, whereas it was normal in a patient with type V glycogenosis. Glucose-1-phosphate level was increased in type VII glycogenosis, whereas it was decreased in type V glycogenosis. Another activator of phosphofructokinase, fructose-2, 6-bisphosphate was increased in muscles of patients with both types of glycogenosis although it was much higher in type VII than in type V. This finding may be partly related to the difference of fructose-6-phosphate concentrations. The results suggest that phosphofructokinase would contribute to the major glucose-1-phosphate kinase activity in normal human muscle and would also form a kind of self-activating system.

Topics: Fructosediphosphates; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VII; Glycolysis; Humans; Muscles; Reference Values

A 60 year old white male presented with atypical chest pain and exercise-induced myalgia. Physical examination revealed slight proximal limb muscle weakness and wasting. Serum creatine phosphokinase levels were persistently elevated and electromyography showed changes consistent with a mild myopathy. Light microscopic and ultrastructural study revealed excess free glycogen within skeletal muscle, and histochemical staining showed absence of myophosphorylase activity. Biochemical quantitation confirmed the diagnosis of McArdle's disease by demonstrating absent phosphorylase activity in skeletal muscle with increased glycogen. In addition, increased amounts of free and membrane-bound glycogen were found within axons, Schwann cells, fibroblasts and occasional vascular smooth muscle and endothelial cells that had been included within the skeletal muscle biopsy. This case demonstrates more widespread glycogen accumulation than has been previously reported in McArdle's disease.

Topics: Biopsy; Blood Vessels; Glycogen; Glycogen Storage Disease Type V; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Muscles; Peripheral Nerves; Phosphorylases

Topics: Diagnosis, Differential; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type IV; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VII; Glycogen Storage Disease Type VIII; Humans

McArdle disease is reported in three generations of a consanguineous Druze family. The diagnosis was established on the basis of a failure of a rise in lactate in the ischemic forearm exercise test, glycogen accumulation in muscle fibers and the lack of myophosphorylase by histochemical and biochemical studies. The inheritance pattern is compatible with an autosomal recessive mode. Examination of family members revealed a marked variability in the clinical findings and functional status. This is the first reported case of the disorder in this ethnic group.

Topics: Adult; Aged; Biopsy; Child, Preschool; Consanguinity; Exercise; Female; Glycogen; Glycogen Storage Disease Type V; Humans; Islam; Lactates; Lactic Acid; Male; Muscles; Pedigree; Phosphorylases

Topics: Adenosine Triphosphate; Amino Acid Sequence; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VII; Hemolysis; Humans; Molecular Sequence Data; Muscles; Uric Acid

Topics: Adolescent; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Humans; Male; Muscles; Myocardium; Phosphorylases

This report deals with structural and biochemical studies of muscle biopsies from six patients with glycogenosis type V (McArdle). From a morphological point of view in four cases the typical findings of vacuolar myopathy with glycogen storage especially under the sarcolemma can be demonstrated. One biopsy shows only mild structural changes which without additional biochemical analysis could be overlooked. In one case signs of recovery phase after rhabdomyolysis predominate the storage myopathy. Biochemical studies in all cases show an elevated glycogen content (2.5-4.23%). Only the from a clinical point of view most expressive patient with recurrent episodes of rhabdomyolysis exhibits a glycogen storage over 5%. All cases additionally show an absence or highly reduction of phosphorylase activity. Apart from the most expressive clinical course the extent of morphological and biochemical findings is not clearly correlated. Therefore if clinical signs suggest the diagnosis of glycogenosis type V it appears necessary to perform additional biochemical examination of muscle biopsy independent from the degree of morphological anomalies.

Topics: Adolescent; Adult; Child; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Humans; Microscopy, Electron; Muscles; Phosphorylase a; Phosphorylase b

We analyzed clinical, histological and biochemical findings in 10 patients with glycogen storage disease in skeletal muscle. Four patients were deficient in acid-alpha-glucosidase (Glycogenosis type II), three of them with late infantile onset and one patient adult form. Five patients, two of them siblings, were deficient in myophosphorylase (glycogenosis type V, McArdle's disease). One patient was a newborn with phosphofructokinase deficiency (glycogenosis type VII, Tarui's disease). Of the study of our cases we would like to outline the following features: in the glycogenosis type II the deposit is fundamentally intralysosomal in the late infantile form, storage of mucopolysaccharides and deposit in interstitial fibroblasts were found, while in the adult form glycogen storage is minimal. In the glycogenosis type V the storage of glycogen is free and of a small amount. In two patients we have observed enzymatic activity in regenerating fibres. In glycogenosis type VII the storage is free, of considerable quantity and the interstitial cells are also affected; no storage is observed in the satellite cells.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type II; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VII; Humans; Male; Muscles; Muscular Diseases

A patient with typical features of late onset McArdle's disease is described. During forearm ischemic work test the patient exhibited an exaggerated increase in ammonia release, largely exceeding normal values. It is suggested, that this is due to an activation of the myokinase/myoadenylate deaminase pathway. Besides lack of lactate release increased ammonia release during ischemia may be a typical feature of McArdle's disease.

Topics: Ammonia; Forearm; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Humans; Ischemia; Lactates; Lactic Acid; Male; Middle Aged; Physical Exertion

The paper reports on three observations made by the authors of McArdle's Disease. Characteristic symptoms are a premature tiring of the musculature and painful muscle contractions; in the late stage of the disease, mild muscle atrophy can also occur. The ischemia test is is pathologic. Myoglobinuria often occurs after major strain. Studies by light microscope and the electron-microscope result in an increased glycogen deposit in the muscle fiber. The diagnosis is verfied by the histochemical and biochemical proof of muscle phosphorylase deficiency. Routine histologic investigation of muscle biopsy is not sufficient to identify the disease. Despite the established enzyme defect and the resulting impairment of anerobic energy availability, the genesis of the disease or syndrome has not yet been fully clarified.

Topics: Adult; Female; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Humans; Middle Aged; Muscles; Myoglobinuria; Physical Exertion

The author describes a family (48 year old mother and 15 year old son) with the muscular variant of glycogenosis-McArde's metabolic myopathy. The mother has been ill since 22 years old, the son--since 7. The disease had a slowly progressive development. The clinical picture was characterized by convulsions of the type of cramps following physical loadings on muscles of the body and extremities. Convulsions were accompanied by pain, an induration and enlargment of the muscles, muscle fatigue and increased significantly in an artifical ischemia of the extremities. A histochemical study of the muscle revealed a pathological accumulation of glycogen. The content of lactic and pyruvic acid in the blood after work in ischemic conditions did not change significantly. A study of the sugar curve in the blood with a loading with glucose and a parallel determination of insulin by a radioimmune method found hyperinsulinemia and a dysfunction of the pancreas.

Topics: Adolescent; Female; Glucose Tolerance Test; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type V; Histocytochemistry; Humans; Lactates; Male; Middle Aged; Muscles; Pyruvates

Topics: Adolescent; Blood Chemical Analysis; Electromyography; Glycogen; Glycogen Storage Disease Type V; Histocytochemistry; Humans; Muscles; Muscular Diseases; Myoglobinuria; Necrosis; Pathology; Phosphotransferases; Physical Exertion; Regeneration; Rhabdomyolysis; Seizures

Topics: Blood; Child; Electromyography; Epinephrine; Fructose; Genetics, Medical; Glucose; Glycogen; Glycogen Storage Disease Type V; Histocytochemistry; Humans; Lactates; Muscular Diseases; Pain; Pathology; Phosphotransferases; Physical Exertion; Pyruvates