Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models

Abstract

GSD are a group of disorders characterized by a defect in gene expression of specific enzymes involved in glycogen breakdown or synthesis, commonly resulting in the accumulation of glycogen in various tissues (primarily the liver and skeletal muscle). Several different GSD animal models have been found to naturally present spontaneous mutations and others have been developed and characterized in order to further understand the physiopathology of these diseases and as a useful tool to evaluate potential therapeutic strategies. In the present work we have reviewed a total of 42 different animal models of GSD, including 26 genetically modified mouse models, 15 naturally occurring models (encompassing quails, cats, dogs, sheep, cattle and horses), and one genetically modified zebrafish model. To our knowledge, this is the most complete list of GSD animal models ever reviewed. Importantly, when all these animal models are analyzed together, we can observe some common traits, as well as model specific differences, that would be overlooked if each model was only studied in the context of a given GSD.

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

“…However, the huge glycogen depots in the skeletal muscle of McArdle mice (20 to 80 times higher than WT mice [ 40 ]) in comparison to patients (2–3 times higher than healthy people [ 87 ]) with subsequent differences in muscle tissue structural alterations represents a major difference between the phenotype of mice and patients. This limitation is also found in other GSD mouse models (e.g., GSD II, III and IV, with >20 times higher glycogen levels than WT mice) [ 49 ] and might be attributable to the faster metabolic rates of these animals, leading to an accelerated accumulation of glycogen in affected tissues. By contrast, in the McArdle bovine and ovine models, muscle glycogen concentrations are 1.6 and 2.2 times higher, respectively, than in control animals [ 46 , 88 ].…”

“…In particular, the ovine model presents a body and muscle mass throughout life that is similar to humans [ 74 ]. However, there are intrinsic difficulties in working with cows and sheep compared to mouse models, such as manipulation, phenotype characterization (e.g., exercise testing), breeding, housing costs, space availability and the possibility of sharing animals between different research groups ( Table 1 ) [ 49 ].…”

“…Another major difference in the disease phenotype between patients and the mouse model is the high frequency of premature death in McArdle mice (~85% of the animals that are born), mainly occurring in the perinatal and post-weaning periods [ 48 , 49 ]. As with the highly elevated glycogen depots, perinatal and post-weaning death has also been reported in different GSD mouse models (GSD 0b, Ia, Ib, IV, VII and XV) [ 48 , 49 ].…”

“…A longitudinal study with 139 matings and more than 2000 offspring showed intrinsic difficulties associated with the management of the McArdle mouse colony basically due to high levels of perinatal and post-weaning mortality [ 48 ]. In this regard, perinatal death has also been observed in GSD-0b, Ia, Ib, IV, VII and XV mouse models [ 49 ], indicating that glycogen might play a crucial role in energy supply during the neonatal period. On the other hand, perinatal death has never been observed in McArdle disease patients.…”

Editorial for Special Issue “Genetic Basis and Epidemiology of Myopathies”

“…According to their findings, a congenital myopathy-causing Q147P substitution in Tpm2.2 disrupts the myosin-induced displacement of tropomyosin over actin, which leads to the premature activation of actin monomers and increases the myosin cross-bridges in a state of strong binding with actin at low Ca 2+ . The fourth paper, titled “Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models”, by [ 4 ] attempts a comprehensive review of animal models of glycogen storage diseases, including genetically modified mouse models, naturally occurring models and a genetically modified zebrafish model. The review highlights both differences and commonalities across the animal models, which contributes to better understanding the models’ advantages and deficiencies.…”