Lysosomal glycogen accumulation in Pompe disease results in disturbed cytoplasmic glycogen metabolism

Rodrigo Canibano-Fraile, Laurike Harlaar, Carlos A Dos Santos, Marianne Hoogeveen-Westerveld, Jeroen A A Demmers, Tim Snijders, Philip Lijnzaad, Robert M Verdijk, Nadine A M E van der Beek, Pieter A van Doorn, Ans T van der Ploeg, Esther Brusse, W W M Pim Pijnappel*, Gerben J Schaaf*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Pompe disease is an inherited metabolic myopathy caused by deficiency of acid α-glucosidase (GAA), resulting in lysosomal glycogen accumulation. Residual GAA enzyme activity affects disease onset and severity, although other factors, including dysregulation of cytoplasmic glycogen metabolism, are suspected to modulate the disease course. In this study, performed in mice and patient biopsies, we found elevated protein levels of enzymes involved in glucose uptake and cytoplasmic glycogen synthesis in skeletal muscle from mice with Pompe disease, including glycogenin (GYG1), glycogen synthase (GS), glucose transporter 4 (GLUT4), glycogen branching enzyme (GBE1), and UDP-glucose pyrophosphorylase (UGP2). Expression levels were elevated before the loss of muscle mass and function. For first time, quantitative mass spectrometry in skeletal muscle biopsies from five adult patients with Pompe disease showed increased expression of glycogen branching enzyme protein relative to healthy controls at the group level. Paired analysis of individual patients who responded well to treatment with enzyme replacement therapy (ERT) showed reduction of glycogen synthase, glycogenin, and glycogen branching enzyme 1 in all patients after start of ERT compared to baseline. These results indicate that metabolic changes precede muscle wasting in Pompe disease, and imply a positive feedforward loop in Pompe disease, in which lysosomal glycogen accumulation promotes cytoplasmic glycogen synthesis and glucose uptake, resulting in aggravation of the disease phenotype.

Original languageEnglish
Pages (from-to)101-115
Number of pages15
JournalJournal of Inherited Metabolic Disease
Issue number1
Early online date16 Sept 2022
Publication statusPublished - Jan 2023


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