Glycogen Metabolism May Go Awry Before Symptoms Appear in Pompe

Enzymes in glycogen metabolism in the cytoplasm are also abnormal in Pompe disease mice, studies show

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A number of enzymes involved in synthesizing glycogen – the molecule that accumulates to toxic levels in Pompe disease – are elevated in a mouse model of the disease and these metabolic changes may contribute to the disease’s progression, a study found.

In fact, the buildup of these proteins occurred even before muscle tissue began to waste away in the mice. Their levels were found to decrease in patients who responded well to enzyme replacement therapy, the mainstay of treatment for Pompe disease, however.

The study, “Lysosomal glycogen accumulation in Pompe disease results in disturbed cytoplasmic glycogen metabolism,” was published in the Journal of Inherited Metabolic Disorder.

Pompe disease is marked by mutations that prevent cells from making enough of the alpha-glucosidase (GAA) enzyme, which is needed to break down a large sugar molecule called glycogen inside lysosomes.

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Lysosomes are structures inside cells where unwanted molecules get recycled or cleared away. These recycling centers contain digestive enzymes, such as GAA, that help degrade faulty and unwanted molecules.

In people with Pompe, the lack of GAA causes glycogen to accumulate inside these structures, leading to a range of symptoms that especially affect the liver, heart, and muscles.

Previous studies have shown that a number of enzymes involved in glycogen metabolism in the cytoplasm are also abnormal in mice with Pompe disease, with those involved in synthesizing the sugar molecule being elevated and those involved in the degradation of glycogen into glucose molecules being reduced.

The findings suggested that mice with the disease have increased levels of glycogen in the cytoplasm that could result in its even greater accumulation in lysosomes and contribute to disease progression.

Researchers in the Netherlands set out to confirm these findings in mice with Pompe disease with a different genetic background, to see if their genetic makeup factored into the results seen in prior research.”

In these mice, where the gene that provides the instructions to make GAA has been removed, the team found that several enzymes involved in glycogen synthesis were increased. These included glycogenin (GYG1), a protein that primes the first molecules of glucose to get together in a molecule of glycogen; glucose transporter 4 (GLUT4), a protein transporter that helps glucose enter into cells; and glycogen branching enzyme (GBE1), which adds branches to a growing glycogen molecule.

These molecular changes were seen as early as 10 weeks of age, before the onset of Pompe symptoms in mice, which typically occurs between 15 and 25 weeks of age, equivalent to people from their 20s to their 30s).

“These results indicate that metabolic changes precede muscle wasting in Pompe disease, and imply a positive feedforward loop in Pompe disease,” the researchers wrote. This means that there may be “changes in glycogen synthesis that may result in accumulation of glycogen also in the cytoplasm in addition to the excess present in the lysosome.”

To determine whether these findings held true in people, the researchers examined muscle tissue from five patients with mild late-onset Pompe disease who responded to ERT within 2–3 years after starting treatment. There were four women and one men with a mean age of 50.8.

Except for GLUT4, which couldn’t be detected in samples, levels of the other four proteins dropped in all patients after the start of ERT. However, levels were not significantly different between patients and a group of healthy controls, likely due to large differences in levels among people from the same group.

These findings suggest proteins involved in glycogen metabolism are “responsive to ERT in skeletal muscle of late-onset Pompe disease patients [who] have a positive response to ERT,” the researchers said.