Low survival rate and muscle fiber-dependent aging effects in the McArdle disease mouse model

Alberto Real-Martinez,John Vissing,Joaquin Arenas,Guillermo Tarrasó,Gisela Nogales-Gadea,Antoni L Andreu,Tomàs Pinós,Miguel Angel Martin,Noemi De Luna,Jordi Huerta,Alejandro Lucia,Thomas O Krag,Astrid Brull

doi:10.1038/s41598-019-41414-8

Abstract

McArdle disease is an autosomal recessive disorder caused by the absence of the muscle glycogen phosphorylase, which leads to impairment of glycogen breakdown. The McArdle mouse, a model heavily affected by glycogen accumulation and exercise intolerance, was used to characterize disease progression at three different ages. The molecular and histopathological consequences of the disease were analyzed in five different hind-limb muscles (soleus, extensor digitorum longus, tibialis anterior, gastrocnemius and quadriceps) of young (8-week-old), adult (35-week-old) and old (70-week-old) mice. We found that McArdle mice have a high perinatal and post-weaning mortality. We also observed a progressive muscle degeneration, fibrosis and inflammation process that was not associated with an increase in muscle glycogen content during aging. Additionally, this progressive degeneration varied among muscle and fiber types. Finally, the lack of glycogen content increase was associated with the inactivation of glycogen synthase and not with compensatory expression of the Pygl and/or Pygb genes in mature muscle.

Highlights

McArdle disease is an autosomal recessive disorder caused by pathogenic mutations in the gene (PYGM) encoding the muscle isoform of glycogen phosphorylase (GP-M, known as myophosphorylase)[1,2]
The number of offspring was significantly different among the distinct matings, showing that a higher presence of the mutant p.R50X allele in parents significantly reduced the number of mice per litter in the offspring (Table 1); the presence of the p.R50X allele in parents was associated with an increased percentage of litters with a 100% mortality (Table 1)
When the offspring mice originating from HTZ x HTZ and McA x HTZ matings were genotyped we observed a clear decrease in the proportion of McA offspring compared to the expected 25% and 50%, respectively, from Mendelian inheritance (Table 2)

Summary

Introduction

McArdle disease (glycogen storage disease V; myophosphorylase deficiency; OMIM database number ♯232600; ORPHA: 368) is an autosomal recessive disorder caused by pathogenic mutations in the gene (PYGM) encoding the muscle isoform of glycogen phosphorylase (GP-M, known as myophosphorylase)[1,2]. Several studies have been performed in the McArdle mouse model, analyzing the disease phenotype in young (8-week-old)[6,7,8,9] or adult mice (20-week-old)[10,11,12] In these studies, it was observed that muscle contractions were affected by structural degeneration due to glycogen accumulation and that glycolytic muscles fatigued prematurely[10]. As disease phenotype progression and its molecular consequences during the aging process remain largely unknown, in the present study we wanted to perform a longitudinal characterization of the McArdle mouse model to determine if the massive glycogen accumulation in myofibers (i) increased with aging and (ii) caused progressive and differential increase in muscle and fiber type degeneration. As we have previously observed an unusually high mortality of McArdle mice[10], we wanted to analyze the survival rate of these mice throughout their life-span

Methods

Results

Conclusion