Muscle Glycogen Phosphorylase and Its Functional Partners in Health and Disease.

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.

Single-centre experience on genotypic and phenotypic features of southern Brazilian patients with McArdle disease.

McArdle disease (MD) is a metabolic myopathy caused by deficiency of the myophosphorylase enzyme. The aim of our study was to analyse a series of MD patients in Brazil and the correlation between clinical findings, laboratory data, electromyography, muscle biopsy and genetic features. The PYGM gene was analysed by PCR/RLFP and Sanger sequencing. The sample included 12 patients, aged 18-57 years, from unrelated families. Exercise intolerance was present in all cases. Serum creatine kinase levels at rest were increased in all patients. Forearm ischaemic exercise testing in five patients revealed no increase in venous lactate. Needle electromyography presented 'myopathic pattern' in six patients. Muscle biopsy showed vacuolar myopathy in 10 patients and deficiency of myophosphorylase enzyme in all patients. The genetic analysis showed p.R50X as the most common mutation (allelic frequency: 56.25%), other known mutations (p.Y574X, p.G205S, p.W798R, IVS14 + 1G > A and IVS19-1G > A) and a new mutation (p.Asn168Lysfs*15) were also identified. Several features of the disorder were similar to the vast majority of patients worldwide. The genetic findings of this study revealed a range of mutations that are quite similar to the European cohort. The discovery of one novel mutation increases the genotypic heterogeneity of PYGM gene.

Muscle diffusion tensor imaging in glycogen storage disease V (McArdle disease).

PURPOSE: To evaluate differences in diffusion parameters in thigh muscles in patients with glycogen storage disease type V (McArdle disease) using muscle diffusion tensor imaging (mDTI) compared to healthy controls METHODS: In this prospective study, we evaluated thigh muscles from hip to knee of 10 McArdle patients (5 female, mean age 33.7 ± 14.4 years) and 10 healthy age- and gender-matched volunteers. MRI scans were performed at 3 T and comprised mDTI, T1-weighted and T2-weighted imaging between May 2015 and May 2017. Needle biopsy of the vastus lateralis muscle was performed in three McArdle patients. The muscle tissue was analyzed by using histochemical and enzyme-histochemical techniques for glycogen content and histopathological changes. Mean values of the eigenvalues (λ1-λ3), fractional anisotropy (FA), and mean diffusivity (MD) were obtained for the vastus lateralis, vastus medialis, rectus femoris, biceps femoris, semitendinosus, and semimembranosus and compared between groups using Student's t tests, as well as ANCOVA; significance level was set at p < 0.05. RESULTS: Needle biopsy showed intracellular glycogen accumulation in skeletal muscle fibers of three McArdle patients. Extracellular histopathological changes were not found. Muscle DTI analysis did not show statistically significant differences between patients and controls for any of the muscles. CONCLUSION: Despite intracellular glycogen accumulation in the three biopsy samples, mDTI parameters were not altered in McArdle patients compared to controls. We conclude that the currently used mDTI acquisition and processing lack the sensitivity to detect intracellular changes due to accumulated glycogen in this cohort of McArdle patients. KEY POINTS: • Despite intracellular glycogen accumulation in three examined biopsy samples, mDTI parameters were not altered in McArdle patients compared to controls. • In its current form, diffusion MR does not provide additional information in quantifying intracellular glycogen accumulations within skeletal muscle fibers in McArdle patients.

Muscle fiber type proportion and size is not altered in mcardle disease.

INTRODUCTION: McArdle disease is a metabolic myopathy that presents with exercise intolerance and episodic rhabdomyolysis. Excessive muscle recruitment has also been shown to be present during strenuous exercise, suggesting decreased power output. These findings could potentially be explained by either impaired contractility, decreased fiber size, or altered fiber type proportion. However, there is a paucity of data on the morphological features seen on muscle histology. METHODS: We examined muscle biopsies of patients with McArdle disease from a Spanish cohort and compared the findings with healthy controls. RESULTS: We found no significant difference in the fiber type proportion or mean fiber size between McArdle patients and controls in the biceps brachii or vastus lateralis muscles. CONCLUSIONS: No alterations in muscle fiber type proportion or size were found on muscle histology of patients with McArdle disease. Future research should focus on assessment of muscle fiber contractility to investigate the functional impairment. Muscle Nerve 55: 916-918, 2017.

Xanthine Oxidase Pathway and Muscle Damage. Insights from McArdle Disease.

The intent of this article is to summarize current body of knowledge on the potential implication of the xanthine oxidase pathway (XO) on skeletal muscle damage. The possible involvement of the XO pathway in muscle damage is exemplified by the role of XO inhibitors (e.g., allopurinol) in attenuating muscle damage. Reliance on this pathway (as well as on the purine nucleotide cycle) could be exacerbated in conditions of low muscle glycogen availability. Thus, we also summarize current hypotheses on the etiology of both baseline and exertional muscle damage in McArdle disease, a condition caused by inherited deficiency of myophosphorylase. Because myophosphorylase catalyzes the first step of muscle glycogen breakdown, patients are unable to obtain energy from their muscle glycogen stores. Finally, we provide preliminary data from our laboratory on the potential implication of the XO pathway in the muscle damage that is commonly experienced by these patients.

Diagnostic power of the non-ischaemic forearm exercise test in detecting glycogenosis type V.

BACKGROUND AND PURPOSE: This was a retrospective study to assess the diagnostic value of the non-ischaemic forearm exercise test in detecting McArdle's disease. METHODS: The study is a retrospective diagnostic study over 15 years (1999-2013) on a referred sample of patients suffering from exercise intolerance and various muscle complaints, generally with elevated creatine kinase (CK). In all, 1226 patients underwent the non-ischaemic forearm exercise test. Blood lactate, ammonia and CK levels were analyzed. DNA analyses and/or muscle biopsies were assessed to confirm the diagnosis of McArdle's disease. The results of 60 volunteers were used to compare with the results of study subjects. RESULTS: In this cohort, 40 patients were finally diagnosed with McArdle's disease. Absolute values of lactate and ammonia rise were used to discriminate all McArdle patients from healthy patients. A sensitivity and specificity of respectively 100% and 99.7% were calculated. The 24-h CK level showed no significant difference from the CK level at the day of the test and confirms the safety of the test. CONCLUSIONS: This study has formally assessed the diagnostic value of the non-ischaemic forearm exercise test in the detection of McArdle's disease. Very high sensitivity and specificity were observed. Furthermore, the test is easy to set up and to perform, it is non-traumatic and cost effective. It may circumvent a muscle biopsy in McArdle patients presenting the most common mutations. Hence, it is a perfect and safe screening instrument to detect patients with McArdle's disease. Glycogen storage disease type III patients, however, may show similar patterns to McArdle patients.

From exercise intolerance to functional improvement: the second wind phenomenon in the identification of McArdle disease.

McArdle disease is the most common of the glycogen storage diseases. Onset of symptoms is usually in childhood with muscle pain and restricted exercise capacity. Signs and symptoms are often ignored in children or put down to 'growing pains' and thus diagnosis is often delayed. Misdiagnosis is not uncommon because several other conditions such as muscular dystrophy and muscle channelopathies can manifest with similar symptoms. A simple exercise test performed in the clinic can however help to identify patients by revealing the second wind phenomenon which is pathognomonic of the condition. Here a patient is reported illustrating the value of using a simple 12 minute walk test.

From exercise intolerance to functional improvement: the second wind phenomenon in the identification of McArdle disease / De intolerância ao exercício à melhora funcional: o fenômeno second wind na identificação da doença de McArdle

McArdle disease is the most common of the glycogen storage diseases. Onset of symptoms is usually in childhood with muscle pain and restricted exercise capacity. Signs and symptoms are often ignored in children or put down to ‘growing pains’ and thus diagnosis is often delayed. Misdiagnosis is not uncommon because several other conditions such as muscular dystrophy and muscle channelopathies can manifest with similar symptoms. A simple exercise test performed in the clinic can however help to identify patients by revealing the second wind phenomenon which is pathognomonic of the condition. Here a patient is reported illustrating the value of using a simple 12 minute walk test.

A doença de McArdle é o tipo mais frequente das glicogenoses. A apresentação clínica característica na infância inclui mialgia e intolerância aos esforços/exercício físico. Frequentemente, os sinais e sintomas das crianças não são considerados devidamente, sendo muitas vezes interpretados como “dores do crescimento”, retardando o diagnóstico. Erros diagnósticos não são raros uma vez que outras doenças, como distrofia muscular ou canalopatias musculares, podem apresentar sintomas semelhantes. Entretanto, um simples teste de exercício físico realizado no ambulatório/consultório médico pode ajudar a identificar estes pacientes pois evidencia o fenômeno second wind, patognomônico da doença de McArdle. Aqui é descrito um relato de caso de um paciente ilustrando o valor do simples 12 minutes walk test.

Confirmation of the efficacy of vitamin B6 supplementation for McArdle disease by follow-up muscle biopsy.

No effective treatment for McArdle disease exists.We report a Japanese patient with McArdle disease who was treated with vitamin B(6) supplementation (60-90 mg/day). After treatment, increased muscle phosphorylase activity was confirmed by follow-up muscle biopsy (3.8 times higher than pretreatment levels). Increased lactate levels were seen on the forearm exercise test, and regular work activities could be resumed. Vitamin B(6) supplementation can enhance residual phosphorylase activity and improve insufficient anaerobic glycolysis of skeletal muscle.

McArdle disease: a clinical review.

METHODS: The clinical phenotype of 45 genetically confirmed McArdle patients is described. RESULTS: In the majority of patients (84%), the onset of symptoms was from early childhood but diagnosis was frequently delayed until after 30 years of age. Not all patients could recognise a second wind although it was always seen with exercise assessment. A history of myoglobinuria was not universal and episodes of acute renal failure had occurred in a minority (11%). The condition does not appear to adversely affect pregnancy and childbirth. Clinical examination was normal in most patients, muscle hypertrophy was present in 24% and mild muscle wasting and weakness were seen only in patients over 40 years of age and was limited to shoulder girdle and axial muscles. The serum creatine kinase was elevated in all but one pregnant patient. Screening for the mutations pArg50X (R50X) and pGly205Ser (G205S) showed at least one mutated allele in 96% of Caucasian British patients, with an allele frequency of 77% for pArg50X in this population. A 12 min walking test to evaluate patients is described. CONCLUSION: The results demonstrated a wide spectrum of severity with the range of distance walked (195-1980 m); the mean distance walked was 512 m, suggesting significant functional impairment in most patients.

Permanent muscle weakness in McArdle disease.

McArdle disease is an autosomal recessive muscle glycogenosis. In the typical clinical presentation, only exercise-related symptoms are noted. Nevertheless, permanent weakness may occur, usually late in life. In this study we report on the clinical and genetic features of fixed muscle weakness in McArdle disease. Among the 80 McArdle patients being followed at the Institute of Myology of the Salpêtrière Hospital, 9 patients have permanent weakness. The diagnosis of McArdle disease was confirmed by muscle biopsy and genetic investigations. Two patterns of muscle weakness and wasting were noted: (1) proximal and symmetric in 5 patients; and (2) asymmetric, mimicking facioscapulohumeral dystrophy (FSHD) in 4 patients. Computerized tomography scan showed fatty infiltration in the shoulder and pelvic girdle muscles. There was no clear correlation between genotype and the severity of muscle weakness. Proximal muscle weakness appeared after the age of 40 years and affected 11% of subjects in our series of 80 McArdle patients. Among patients over 40 years of age, 37.5% had muscle weakness.

[Metabolic myopathies - an overview]. / Metabolische Myopathien - ein Uberblick.

Metabolic disorders of energy production characterise the group of rare, mainly autosomal recessively inherited metabolic muscular diseases which are often associated with multi-systemic symptoms. In this report, an update on the clinics, pathophysiology, pathomorphology and current treatment options of metabolic myopathies will be given. Beyond classic phenotypes of these disorders, one should be aware of oligosymptomatic patients who can be easily missed. The relevant gene mutations and the pathophysiology and pathomorphology they cause are now known for almost all these metabolic diseases. Establishing the correct diagnosis has become even more important since highly specific therapy options are now available for at least some of these inherited disorders, e.g. enzyme replacement therapy in Pompe disease.

Adenovirus and adeno-associated virus-mediated delivery of human myophosphorylase cDNA and LacZ cDNA to muscle in the ovine model of McArdle's disease: expression and re-expression of glycogen phosphorylase.

At present there is no satisfactory treatment for McArdle's disease, deficiency of myophosphorylase. Injection of modified adenovirus 5 (AdV5) and adeno-associated virus 2 (AAV2) vectors containing myophosphorylase expression cassettes, into semitendinosus muscle of sheep with McArdle's disease, produced expression of functional myophosphorylase and some re-expression of the non-muscle glycogen phosphorylase isoforms (both liver and brain) in regenerating fibres. Expression of both non-muscle isoforms was also seen after control injections of AdV5LacZ vectors. There was up to an order of magnitude greater expression of phosphorylase after myophosphorylase vector injection than after LacZ controls (62% of sections with over 1000 positive muscle fibres, versus 7%). The results presented here suggest that the use of viral vector-mediated phosphorylase gene transfer may be applicable to the treatment of McArdle's disease and that sustained re-expression of the brain and liver isoforms should also be investigated as a possible treatment.

McArdle disease with rhabdomyolysis induced by rosuvastatin: case report.

The rosuvastatin inducing rhabdomyolysis in McArdle disease (MD) has not been reported to date. A 35-years-old man had exercise intolerance, muscular fatigue and cramps during physical activity since infancy. He presented severe rhabdomyolysis episode with seizure and coma after use of rosuvastatin. The investigation showed increased serum creatine-kinase levels and the forearm ischemic exercise did not increase venous lactate. The muscle biopsy showed subsarcolemmal and central accumulation of glycogen and absence of the myophosphorylase enzyme. The statin induced myopathy is discussed and the danger of its use in MD is emphasized.

McArdle disease with rhabdomyolysis induced by rosuvastatin: case report

The rosuvastatin inducing rhabdomyolysis in McArdle disease (MD) has not been reported to date. A 35-years-old man had exercise intolerance, muscular fatigue and cramps during physical activity since infancy. He presented severe rhabdomyolysis episode with seizure and coma after use of rosuvastatin. The investigation showed increased serum creatinekinase levels and the forearm ischemic exercise did not increased venous lactate. The muscle biopsy showed subsarcolemmal and central acummulation of glycogen and absence of the myophosphorylase enzyme. The statin induced myopathy is discussed and the danger of its use in MD is emphasized.

Rosuvastatina induzindo rabdomiólise na doença de McArdle (MD) não foi relatada até o momento. Descrevemos o caso de um homem de 35 anos que desde a infância apresentava sintomas de intolerância aos exercícios, fadiga muscular e cãibras durante o esforço físico, porém após o uso de rosuvastatina apresentou episódio de rabdomiólise com crises convulsivas e coma. A investigação mostrou creatinoquinase sérica elevada e teste do esforço isquêmico sem aumento no lactato venoso. A biópsia muscular revelou acúmulo central e subsarcolemal de glicogênio nas fibras e ausência da enzima miofosforilase. Discutimos as estatinas induzindo miopatia, enfatizando o risco do seu uso na MD.

[Motor nerve conduction study in McArdle disease: case report]. / Estudo da condução nervosa motora na doença de McArdle: relato de caso.

McArdle disease (glycogenosis type V) is a metabolic myopathy with symptoms of exercise intolerance caused by deficiency of the enzyme myophosphorylase. In these patients, the motor nerve conduction studies after a short period of maximal voluntary muscle contraction or repetitive stimulation reveals characteristic findings of the disease. A 37-year-old man presented symptoms of exercise intolerance, muscular fatigue and cramps in the beginning of the physical activity with "second wind" phenomenon. The motor nerve conduction studies after a voluntary contraction of 30 and 90 seconds presented decrease in the amplitude of the compound muscle action potential in median, ulnar and deep peroneal nerves; and decrement after 200 stimulation at the 40 Hz in deep peroneal nerve. The electromyography presented myopathic pattern and during the ischemic exercise electric silence was not proven. The characteristic of electrophysiological studies are discussed with emphasis at the importance of the motor nerve conduction studies in the patients with suspicion of metabolic myopathy.

Estudo da condução nervosa motora na doença de McArdle: relato de caso / Motor nerve conduction study in McArdle disease: case report

McArdle disease (glycogenosis type V) is a metabolic myopathy with symptoms of exercise intolerance caused by deficiency of the enzyme myophosphorylase. In these patients, the motor nerve conduction studies after a short period of maximal voluntary muscle contraction or repetitive stimulation reveals characteristic findings of the disease. A 37-year-old man presented symptoms of exercise intolerance, muscular fatigue and cramps in the beginning of the physical activity with [quot ]second wind[quot ] phenomenon. The motor nerve conduction studies after a voluntary contraction of 30 and 90 seconds presented decrease in the amplitude of the compound muscle action potential in median, ulnar and deep peroneal nerves; and decrement after 200 stimulation at the 40 Hz in deep peroneal nerve. The electromyography presented myopathic pattern and during the ischemic exercise electric silence was not proven. The characteristic of electrophysiological studies are discussed with emphasis at the importance of the motor nerve conduction studies in the patients with suspicion of metabolic myopathy.

A doença de McArdle (glicogenose tipo V) é miopatia metabólica com sintomas de intolerância ao exercício, causados pela deficiência da enzima miofosforilase. Nesses pacientes, o estudo da condução nervosa motora após período de esforço muscular máximo ou ao estímulo repetitivo pode revelar achados característicos da doença. Descrevemos o caso de um homem de 37 anos com sintomas de intolerância aos exercícios, fadiga muscular e cãibras no início da atividade física com a presença do fenômeno de "second wind". O estudo da condução nervosa motora apresentava redução na amplitude do potencial de ação muscular composto após esforço de 30 e 90 segundos em nervos mediano, ulnar e fibular profundo e decremento após 200 estímulos a 40 Hz em nervo fibular profundo. A eletromiografia de agulha apresentava padrão miopático e durante o exercício isquêmico não se evidenciou silêncio elétrico. Discutimos as características eletrofisiológicas enfatizando a importância do estudo da condução nervosa motora e teste de estimulação repetitiva nos pacientes com suspeita de miopatia metabólica.

Phenotype modulators in myophosphorylase deficiency.

Myophosphorylase deficiency is characterized by exercise intolerance, muscle cramps, and recurrent myoglobinuria. Some patients are severely affected, whereas others are minimally affected or asymptomatic. The molecular basis of the disease has been elucidated but does not provide an explanation for the clinical variability. In a large cohort of patients with myophosphorylase deficiency, we tested the hypothesis that polymorphic variants in either myoadenylate deaminase (MADA) or angiotensin-converting enzyme (ACE) could act as modulators of phenotype expression. Forty-seven patients were evaluated. Clinical severity was assessed according to a severity scale of four grades. MADA activity was studied by histochemical and biochemical analysis of muscle, and the Q12X mutation in the adenine monophosphate deaminase 1 gene (AMPD1) and the insertion/deletion polymorphism in the ACE gene were assessed genetically. A complete MADA defect together with the Q12X mutation was detected in one severely affected patient. Eleven patients were heterozygous for the Q12X mutation. There was no association between clinical grading and MADA status. In contrast, we found a highly significant (p < 0.01) association between ACE genotype and clinical severity, with strong correlation between severe phenotype and number of D alleles. We show that ACE insertion/deletion polymorphism may play a significant role as phenotype modulator in McArdle's disease.

McArdle's disease presenting with asymmetric, late-onset arm weakness.

McArdle's disease or myophosphorylase deficiency is one of the most common muscle glycogenoses and typically presents in childhood or adolescence with exercise intolerance, myalgia, myoglobinuria, and cramps in exercising muscle. We describe an elderly man who developed asymmetric proximal arm weakness at age 73. He had no history of exercise-induced cramps, myalgias, or myoglobinuria. Creatine kinase levels were elevated, serum lactate did not rise on ischemic exercise testing, and muscle biopsy showed a vacuolar myopathy with absent myophosphorylase activity. This unusual case demonstrates that McArdle's disease may present with fixed, asymmetric proximal weakness at an advanced age and should be considered in this clinical setting, especially when a history of poor exercise tolerance can be elicited.

Selective atrophy of type 1 muscle fibers in McArdle's disease.

McArdle's disease is a metabolic myopathy of glycogen utilization caused by an absence or deficiency of myophosphorylase. The muscle biopsy features include increased deposition of subsarcolemmal glycogen and absent phosphorylase histochemical staining of myofibers. We report the clinical and unique pathologic findings in three cases of McArdle's disease with prominent type 1 fiber atrophy.