Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases

Cell Rep. 2019 Apr 30;27(5):1334-1344.e6. doi: 10.1016/j.celrep.2019.04.017.


Lafora disease (LD) and adult polyglucosan body disease (APBD) are glycogen storage diseases characterized by a pathogenic buildup of insoluble glycogen. Mechanisms causing glycogen insolubility are poorly understood. Here, in two mouse models of LD (Epm2a-/- and Epm2b-/-) and one of APBD (Gbe1ys/ys), the separation of soluble and insoluble muscle glycogen is described, enabling separate analysis of each fraction. Total glycogen is increased in LD and APBD mice, which, together with abnormal chain length and molecule size distributions, is largely if not fully attributed to insoluble glycogen. Soluble glycogen consists of molecules with distinct chain length distributions and differential corresponding solubility, providing a mechanistic link between soluble and insoluble glycogen in vivo. Phosphorylation states differ across glycogen fractions and mouse models, demonstrating that hyperphosphorylation is not a basic feature of insoluble glycogen. Lastly, model-specific variances in protein and activity levels of key glycogen synthesis enzymes suggest uninvestigated regulatory mechanisms.

Keywords: APBD; Lafora disease; glycogen branching enzyme; glycogen chain length distribution; glycogen storage disease; glycogen synthase; laforin; malin; phosphorylation; polyglucosan bodies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Glycogen / chemistry
  • Glycogen / metabolism*
  • Glycogen Debranching Enzyme System / genetics
  • Glycogen Storage Disease / genetics
  • Glycogen Storage Disease / metabolism*
  • HEK293 Cells
  • Humans
  • Lafora Disease / genetics
  • Lafora Disease / metabolism*
  • Male
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Nervous System Diseases / genetics
  • Nervous System Diseases / metabolism*
  • Phosphorylation
  • Solubility


  • Emp2 protein, mouse
  • Glycogen Debranching Enzyme System
  • Membrane Glycoproteins
  • Glycogen

Supplementary concepts

  • Polyglucosan Body Disease, Adult Form