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

9 Citations (Scopus)
46 Downloads (Pure)


Pompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha-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 (GYS1), glucose transporter 4 (GLUT4), glycogen branching enzyme 1 (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 GBE1 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 GYS1, GYG1, and GBE1 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

Bibliographical note

Funding Information:
The work was funded by a grant from the EU Joint Programme Neurodegenerative Disease research (JPND); and by a research grant from Sanofi Genzyme to the Center for Lysosomal and Metabolic Diseases at Erasmus MC.

Funding Information:
Research grant from Sanofi Genzyme; Research grant from EU Joint Programme Neurodegenerative Disease Research (JPND) Funding information

Publisher Copyright:
© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.


Dive into the research topics of 'Lysosomal glycogen accumulation in Pompe disease results in disturbed cytoplasmic glycogen metabolism'. Together they form a unique fingerprint.

Cite this