Analysis of the structural and metabolic consequences of McArdle disease using the murine model

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 observed 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. 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. Furthermore, the molecular interconnection between skeletal muscle-liver and adipose tissue was assessed in these mice in order to determine whether there was an upregulation of the oxidative metabolism during disease progression as McArdle mice presented a clear reduction in abdominal fat and liver glycogen content. In this regard, mitochondrial content and activity were assessed in both oxidative and glycolytic muscles as oxidative fibers (specially IIa fibers) presented more structural damage caused by higher glycogen accumulation than glycolytic fibers (IIx and IIx/IIb fibers). Lower levels of mitochondrial content and activity were found in the skeletal muscle of McA mice with respect to their wild-type counterparts.