Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies

Abstract

McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute “crises” of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient’s phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients.

Long-Term Exercise Intervention in Patients with McArdle Disease: Clinical and Aerobic Fitness Benefits

“…However, regular physical exercise during half this period can restore almost full functional capacity in these patients, at least during activities of daily living, as suggested by the present findings. This is an important consideration when keeping in mind that no molecular therapy is predicted to have such beneficial effect in the foreseeable future-that is, no drug is likely to ensure long-lasting restoration of myophosphorylase (even residual) activity, as recently reviewed by us in depth regarding published and ongoing preclinical therapeutic trials (26). Our results are consistent with previous noncontrolled research from our group, where a resistance training-only intervention reduced clinical severity in one adolescent (27) or in seven adults with McArdle disease (13).…”

Identification of kukoamine a as an anti-osteoporosis drug target using network pharmacology and experiment verification

“…However, it is expressed in tissues other than muscle, such as the bone, brain, lymphoid tissues, and blood. PYGM also played an important role in a variety of diseases such as early fatigue, myalgia, and contractures (Villarreal-Salazar et al 2021 ; Gomes et al 2020 ; Jin and Yang 2019 ; Nogales-Gadea et al 2015 ). PYGM was identified as a candidate gene that may play an important role in BMD regulation in women (He et al 2016 ).…”

Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the PYGM Gene

“…To date, there is no cure for McArdle disease and the only treatments available are focused on mitigating symptoms, such as controlled and supervised exercise or pre-exercise nutritional supplementation. Furthermore, although the models available to study the disease have allowed us to better understand its pathophysiological mechanisms and even test possible drugs for its treatment, none of them have been useful for high-throughput pharmacological screening studies [ 16 ].…”