Abstract
McArdle disease, also known as glycogen storage disease type V (GSDV), is characterized by exercise intolerance, the second wind phenomenon, and high serum creatine kinase activity. Here, we recapitulate PYGM mutations in the population responsible for this disease. Traditionally, McArdle disease has been considered a metabolic myopathy caused by the lack of expression of the muscle isoform of the glycogen phosphorylase (PYGM). However, recent findings challenge this view, since it has been shown that PYGM is present in other tissues than the skeletal muscle. We review the latest studies about the molecular mechanism involved in glycogen phosphorylase activity regulation. Further, we summarize the expression and functional significance of PYGM in other tissues than skeletal muscle both in health and McArdle disease. Furthermore, we examine the different animal models that have served as the knowledge base for better understanding of McArdle disease. Finally, we give an overview of the latest state-of-the-art clinical trials currently being carried out and present an updated view of the current therapies.
Highlights
McArdle disease, known as glycogen storage disease type V (GSDV; MIM#232600), is a severe form of glycogen storage disorder
Different isoforms of adenylyl cyclase (AC) can be activated by both Ca2+ and direct phosphorylation due to the action of protein kinase A (PKA) and/or protein kinase C (PKC) [24], or Raf-1 [25,26]. In this fashion and in regard to the canonical pathway of glycogen phosphorylase activation, Llavero et al have recently described the relationship between the epidermal growth factor receptor (EGFR) and glycogen phosphorylase activation
The results reported by Rodríguez-Gómez et al suggest possible comorbidities with McArdle disease, as they show an undescribed condition in McArdle patients, who presented lower lean mass (LM) values in whole-body and regional sites, bone mineral content (BMC), and density (BMD) [53]
Summary
McArdle disease, known as glycogen storage disease type V (GSDV; MIM#232600), is a severe form of glycogen storage disorder. Glycogen phosphorylase (PYG) is the enzyme that catalyzes the first step of glycogenolysis to release glucose-1-phosphate (G1P) monomers from the intracellular glycogen stores [1] This disease is included within the rare diseases category, and the exact prevalence is not known, it has been estimated to be 1 in 100,000–140,000 patients [4,5]. The first symptoms occur during childhood and manifest as a syndrome of intolerance to exercise, cramps, fatigue, and muscle weakness. A “recovery” phenomenon known as the second-wind phenomenon is observed in many patients with relief of myalgia and fatigue after a few minutes of resting [7,8] This clinical picture is usually standard, but some patients may manifest moderate or severe forms. Ketogenic and protein-rich diets only had beneficial effects when the patients had already suffered an episode of rhabdomyolysis [5,10,11]
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