Sports and McArdle Disease (Glycogen Storage Disease Type V): Danger or Therapy?

McArdle disease (glycogen storage disease type V) is an inborn error of energy metabolism in the muscle. The effects of McArdle disease on physical performance have similarities with the metabolic state of marathon runners after glycogen depletion and can therefore be seen as a nature’s experiment in the field of sports medicine. Many patients with McArdle disease avoid sports in general because physical activity usually leads to muscle pain and muscle cramps. Often patients therefore regard physical activity as both painful and possibly dangerous. This chapter is about the advantages and possible risks of sports for patients with McArdle disease. The scientific literature will be discussed highlighting both endurance and muscle strength exercise. It will discuss the differences of aerobic and anaerobic exercise in individuals suffering from McArdle disease. Complications as rhabdomyolysis, myoglobinuria, kidney failure, and malignant hyperthermia will be discussed. The chapter will summarize the current knowledge about the possible dangers versus possible benefits of sports for patients with McArdle disease. A summary of recommendations for physical exercise and training for McArdle patients will be provided

Translational Research Studies in Exercise-related Muscle Disorders

Translational research is the process that transfers knowledge from basic sciences to the clinical setting. This PhD thesis translates knowledge gained from animal model research in hypokalaemic periodic paralysis (HypoPP) and McArdle disease to humans affected by these conditions to identify new treatment options for both diseases. The efficacy of two compounds, sodium valproate and bumetanide, were assessed for the first time in humans with McArdle disease and HypoPP, respectively. For HypoPP, the role of the McManis test as an outcome measure was explored in a randomised, double-blind, placebo-controlled phase II clinical trial with a cross-over design. For McArdle disease, several outcome measures were explored in an open-label proof-of-concept phase II study. 2 mg bumetanide was not effective to abort a focal attack of weakness in an immobilised hand in the majority of the trial participants with HypoPP, but data presented here supports further studies of bumetanide in this population of patients. Extending the isometric exercise period to 10 minutes increased the sensitivity of the McManis test, and frequent compound muscle action potential (CMAP) amplitude assessments were shown to be useful in assessing both efficacy and safety. 20 mg/kg/day sodium valproate was ineffective in stimulating the expression of the brain glycogen phosphorylase enzyme in skeletal muscle of people with McArdle disease. Based on these results, further research into VPA as a treatment for McArdle disease is discouraged. The combination of several outcome measures contributed to data interpretation and should be considered in future studies exploring treatment efficacy in McArdle disease. The results of this research should contribute to future clinical trials in the field of exercise-related muscle disorders and provide valuable insights for translational research

Results of an open label feasibility study of sodium valproate in people with McArdle disease

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy. Animal model studies indicate that sodium valproate (VPA) can increase expression of phosphorylase in skeletal muscle affected with McArdle disease. This study was designed to assess whether VPA can modify expression of brain phosphorylase isoenzyme in people with McArdle disease. This phase II, open label, feasibility pilot study to assess efficacy of six months treatment with VPA (20 mg/kg/day) included 16 people with McArdle disease. Primary outcome assessed changes in VO2peak during an incremental cycle test. Secondary outcomes included: phosphorylase enzyme expression in post-treatment muscle biopsy, total distance walked in 12 min, plasma lactate change (forearm exercise test) and quality of life (SF36). Safety parameters. 14 participants completed the trial, VPA treatment was well tolerated; weight gain was the most frequently reported drug-related adverse event. There was no clinically meaningful change in any of the primary or secondary outcome measures including: VO2peak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. Although this was a small open label feasibility study, it suggests that a larger randomised controlled study of VPA, may not be worthwhile

Resistance Exercise Training in McArdle Disease: Myth or Reality?

McArdle disease is a metabolic myopathy mainly characterised by symptom onset during physical activities or isometric muscle contraction. Resistance (also termed strength) training is a type of physical exercise focusing on the use of resistance (e.g., lifing weights) to induce muscular contraction, which builds muscle mass and strength. Historically people with McArdle disease were advised to avoid resistance exercises and any other form of physical activity involving high mechanical loads such as prolonged isometric contraction. Paradoxically, a clinical trial exploring the benefts of strength training in this patient population was published. Te theory supporting strength training relied on the use of the ATP molecule and the creatine phosphate (ATPphosphocreatine system) as energy sources for skeletal muscles. Here, we report two patients with McArdle disease who performed weight training at local gyms. A single set of repetitions lasted for maximum 10 seconds with minimum of 30 seconds of rest period in between sets of exercises. Benefts of this type of training included improvement in quality of life and amelioration of McArdle disease symptoms. We provide further safety evidence of this type of exercise in people with McArdle disease. We emphasise the importance of using a specifc protocol developed for people afected by this condition

Generation of the first human in vitro model for McArdle disease based on iPSC Technology

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.This work has been funded by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (ISCIII): PI15/00484, CP16/00046 and PI18/00151 to MEG and PI17/02052 to JA (co-funded by European Regional Development Fund “A way to make Europe”); PI21/00162 and CPII21/00011 co-funded by the European Union to MEG. MdCOC receives grant support from the ‘Ministerio de Educación, Cultura y Deporte’ (FPU16/03895), ‘Fundación para la Investigación Biomédica Hospital 12 de Octubre’ (2022/0065, i+12-AY20220114-1) and EMBO Grant 8917. CL and MD were recipient of a fellowship from the French Ministry of Education. The work in FM’s laboratory was funded by “Association Française contre les Myopathies” (AFM; TRIM-RD and MoThARD) and from the Excellence Initiative of Aix-Marseille University-A*Midex, a French “investissement d’avenir programme” AMX-19-IET-007 through the Marseille Maladies Rares (MarMaRa) Institute (phD fellowship to CL)

Discovery in Medicine

In this chapter, I discuss the discovery of McArdle disease. I then use two philosophical account of discovery – one by Thomas Kuhn, the other by Norwood Hanson – to argue against the idea that discovery is merely a psychological phenomenon

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.RSS is funded by Ciências sem Fronteiras/CAPES Foundation. The authors would like to thank the Association for Glycogen Storage Disease (UK), the EUROMAC Registry funded by the European Union, the Muscular Dystrophy Campaign, the NHS National Specialist Commissioning Group and the Myositis Support Group for funding

McArdle disease: mutational spectrum of Portuguese patients

McArdle disease or Glycogen Storage Disease type V (GSD V; myophosphorylase deficiency; MIM 232600) its an inborn error of glycogen metabolism, caused by a deficiency in muscle specific isoform of glycogen phosphorylase. This metabolic myopathy is characterised by exercise intolerance, myalgia, cramps and episodic myoglobinuria, symptoms that usually appear during the second or third decade of life. The diagnosis was typically made in muscle biopsy by histological analysis (demonstration of subsarcolemmal glycogen deposits and negative histochemical stain for phosphorylase) and/or measurement of muscle phosphorylase activity. Although since 1984, when the gene of muscle isoform of phosphorylase (myophosphorylase) was cloned and assigned to chromosome 11 (11q13), molecular genetics analysis has been more and more used to confirm the clinical diagnosis. Until now, 146 pathogenic mutations have been described (according to HGMDTM) including nonsense, missense and framshift mutations. High genetic heterogeneity is a hallmark of McArdle disease with a very frequent common mutation among Caucasian populations – R49X (present in about 60% of the mutated alleles) – and several rare mutations, without a clear genotype/phenotype correlation. The authors will present molecular data from the characterisation of 53 Portuguese patients, from 42 families, with McArdle disease. Our results reveal the presence of the R49X mutation in 60 of the alleles (57%), in accordance to what has been described to other Caucasian populations, being identified a total of 15 different mutations were identified. These results allowed in many cases the diagnosis without the need of a muscle biopsy, but also provide valuable information for genetic counselling and to increase the knowledge about the molecular pathology of this disorder

Identification of Potential Muscle Biomarkers in McArdle Disease: Insights from Muscle Proteome Analysis

McArdle disease; Proteomics; Skeletal muscleEnfermedad de McArdle; Proteómica; Músculo esqueléticoMalaltia de McArdle; Proteòmica; Múscul esquelèticGlycogen 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.This research was funded by Instituto de Salud Carlos III (ISCIII) y FEDER (ERDF) funds “a way to construct Europe”; Ministerio de Ciencia e Innovación (Madrid, Spain), grant numbers (PI17/02052 and PI19/01313). G.N.-G is supported by a ISCIII contract CPII19/00021. P.S.-L. is supported by a ISCIII-CIBERER contract

Unique Exercise Lactate Profile in Muscle phosphofructokinase Deficiency (Tarui Disease); Difference Compared with McArdle Disease

Introduction: Glycogen storage disease V (GSDV, McArdle disease) and GSDVII (Tarui disease) are the most common of the rare disorders of glycogen metabolism. Both are associated with low lactate levels on exercise. Our aim was to find out whether lactate response associated with exercise testing could distinguish between these disorders. Methods: Two siblings with Tarui disease, two patients with McArdle disease and eight healthy controls were tested on spiroergometric exercise tests with follow-up of venous lactate and ammonia. Results: A late increase of lactate about three times the basal level was seen 10-30 min after exercise in patients with Tarui disease being higher than in McArdle disease and lower than in the controls. Ammonia was increased in Tarui disease. Discussion: Our results suggest that follow-up of lactate associated with exercise testing can be utilized in diagnostics to distinguish between different GSD diseases.Peer reviewe