PYGM, encoding muscle glycogen phosphorylase, is a key enzyme in the first step of glycogenolysis, catalyzing the release of glucose-1-phosphate from glycogen deposits, thus playing a crucial role in muscle metabolism [2,4]. Mutations in this gene lead to autosomal-recessive McArdle disease, highlighting its significance in normal muscle function [2,4]. Zebrafish and mouse models have been used to study PYGM due to their similarities to human muscle and the ability to model the disease [1,4].

In a knock-in mouse model for the p.R50X mutation in the Pygm gene, no detectable read-through of the premature termination codon was found with various read-through agents, despite a potentially favorable stop codon context for read-through induction [1]. In zebrafish, knockdown of Pygm (Pygma and Pygmb) led to reduced Pygm levels, altered muscle structure, and glycogen granule accumulation, mimicking human McArdle disease symptoms [4]. Also, in an AD model, down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice, while overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice, indicating its role in synaptic function and energy generation in neurons [3].

In conclusion, PYGM is essential for muscle glycogen breakdown and normal muscle function, as demonstrated by disease-related mutations and animal models. Mouse and zebrafish models have been valuable in understanding its role in McArdle disease, while studies in an AD model have shown its significance in synaptic function. These model-based studies contribute to our understanding of the biological functions of PYGM and its implications in specific disease areas [1,3,4].

References:

1. Tarrasó, Guillermo, Real-Martinez, Alberto, Parés, Marta, Krag, Thomas O, Pinós, Tomàs. 2020. Absence of p.R50X Pygm read-through in McArdle disease cellular models. In Disease models & mechanisms, 13, . doi:10.1242/dmm.043281. https://pubmed.ncbi.nlm.nih.gov/31848135/

2. Nogales-Gadea, Gisela, Brull, Astrid, Santalla, Alfredo, de Luna, Noemi, Pinós, Tomàs. 2015. McArdle Disease: Update of Reported Mutations and Polymorphisms in the PYGM Gene. In Human mutation, 36, 669-78. doi:10.1002/humu.22806. https://pubmed.ncbi.nlm.nih.gov/25914343/

3. Wang, Ting, Zhou, Yun-Qiang, Wang, Yong, Wang, Zhan-Xiang, Zhang, Yun-Wu. . Long-term potentiation-based screening identifies neuronal PYGM as a synaptic plasticity regulator participating in Alzheimer's disease. In Zoological research, 44, 867-881. doi:10.24272/j.issn.2095-8137.2023.123. https://pubmed.ncbi.nlm.nih.gov/37537141/

4. Migocka-Patrzałek, Marta, Lewicka, Anna, Elias, Magdalena, Daczewska, Małgorzata. 2019. The effect of muscle glycogen phosphorylase (Pygm) knockdown on zebrafish morphology. In The international journal of biochemistry & cell biology, 118, 105658. doi:10.1016/j.biocel.2019.105658. https://pubmed.ncbi.nlm.nih.gov/31747538/