Differential Muscle Involvement in Mice and Humans Affected by McArdle Disease

Abstract

McArdle disease (muscle glycogenosis type V) is caused by myophosphorylase deficiency, which leads to impaired glycogen breakdown. We investigated how myophosphorylase deficiency affects muscle physiology, morphology, and glucose metabolism in 20-week-old McArdle mice and compared the findings to those in McArdle disease patients. Muscle contractions in the McArdle mice were affected by structural degeneration due to glycogen accumulation, and glycolytic muscles fatigued prematurely, as occurs in the muscles of McArdle disease patients. Homozygous McArdle mice showed muscle fiber disarray, variations in fiber size, vacuoles, and some internal nuclei associated with cytosolic glycogen accumulation and ongoing regeneration; structural damage was seen only in a minority of human patients. Neither liver nor brain isoforms of glycogen phosphorylase were upregulated in muscles, thus providing no substitution for the missing muscle isoform. In the mice, the tibialis anterior (TA) muscles were invariably more damaged than the quadriceps muscles. This may relate to a 7-fold higher level of myophosphorylase in TA compared to quadriceps in wild-type mice and suggests higher glucose turnover in the TA. Thus, despite differences, the mouse model of McArdle disease shares fundamental physiological and clinical features with the human disease and could be used for studies of pathogenesis and development of therapies.

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

“…Biopsies from Patients I-1 and I-2 were processed for sodium dodecyl sulfatepolyacrylamide gel electrophoresis and Western blotting as previously described 21 and incubated with antibodies against POPDC1, POPDC2, POPDC3 (Abcam, Cambridge, UK), and TREK-1 (Sigma-Aldrich, St Louis, MO) with vinculin (Abcam) as loading control. Goat antirabbit horseradish peroxidase was used as a secondary antibody (Thermo Fisher Scientific, Waltham, MA), and the blots were developed using Clarity Max (Bio-Rad Laboratories, Hercules, CA).…”

Differential glucose metabolism in mice and humans affected by McArdle disease

“…The dual absence of a decrease in insulin-dependent and increase in AMPK-mediated glucose uptake compounds the problem with glucose metabolism in the soleus, EDL, and TA, as it favors glycogen synthesis without providing a compensating way of accessing and metabolizing glucose. The dependency on glucose from glycogen is strikingly different between TA and quadriceps, as TA has a seven times higher level of myophosphorylase than quadriceps (9).…”

“…In addition, Akt-and AMPK-mediated glucose uptake takes place through phosphorylation of the GLUT4 storage vesicles associated TBC1D1/TBC1D4 proteins, which are then released from the vesicles, leading to vesicle-membrane fusion (5). In the McArdle mouse, fiber type distribution in soleus, EDL, and TA favor insulin-induced glucose uptake and glycogen synthesis, leading to massive glycogen accumulation due to an absence of a coherent change in glucose metabolism (9). Soleus is affected as well due to its content of mixed or pure type IIA and IIX MHC fibers.…”

“…We have previously characterized muscle function and histopathology in the adult McArdle mouse (20 wk old) and found that both fastand slow-twitch muscles are affected by both structural degeneration and energy deficiency (9). In this regard, massive structural damage is evident in the McArdle mouse, causing degeneration and regeneration of the muscle.…”

“…However, glycogen accumulation was not seen at all in pure MHC type I slow oxidative fibers and rarely seen in fibers containing a mix of MHC IIX/IIB or pure MHC IIB fibers, which make up the majority of fibers in the highly glycolytic quadriceps muscle. A comprehensive histological study of the soleus muscle and for comparison, three glycolytic muscles such as tibialis anterior (TA), extensor digitorum longus (EDL), and quadriceps from the McArdle mouse revealed that only the latter was spared from a devastating glycogen accumulation (9). Although the soleus is considered an oxidative muscle, with a majority of fibers being MHC type I, I/IIA or IIA, there are a considerable number of glycolytic fibers containing MHC type IIA/IIX and IIX, which would explain why the soleus was severely affected by the glycogen accumulation.…”