Muscle glycogen remodeling and glycogen phosphate metabolism following exhaustive exercise of wild type and laforin knockout mice

Jose M. Irimia, Vincent S. Tagliabracci, Catalina M. Meyer, Dyann M. Segvich, Anna De Paoli-Roach, Peter Roach

Research output: Contribution to journalArticle

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Abstract

Glycogen, the repository of glucose in many cell types, contains small amounts of covalent phosphate, of uncertain function and poorly understood metabolism. Loss-of-function mutations in the laforin gene cause the fatal neurodegenerative disorder, Lafora disease, characterized by increased glycogen phosphorylation and the formation of abnormal deposits of glycogenlike material called Lafora bodies. It is generally accepted that the phosphate is removed by the laforin phosphatase. To study the dynamics of skeletal muscle glycogen phosphorylation in vivo under physiological conditions, mice were subjected to glycogen-depleting exercise and then monitored while they resynthesized glycogen. Depletion of glycogen by exercise was associated with a substantial reduction in total glycogen phosphate and the newly resynthesized glycogen was less branched and less phosphorylated. Branching returned to normal on a time frame of days, whereas phosphorylation remained suppressed over a longer period of time. We observed no change in markers of autophagy. Exercise of 3-month-old laforin knockout mice caused a similar depletion of glycogen but no loss of glycogen phosphate. Furthermore, remodeling of glycogen to restore the basal branching pattern was delayed in the knockout animals. From these results, we infer that 1) laforin is responsible for glycogen dephosphorylation during exercise and acts during the cytosolic degradation of glycogen, 2) excess glycogen phosphorylation in the absence of laforin delays the normal remodeling of the branching structure, and 3) the accumulation of glycogen phosphate is a relatively slow process involving multiple cycles of glycogen synthesis-degradation, consistent with the slow onset of the symptoms of Lafora disease.

Original languageEnglish (US)
Pages (from-to)22686-22698
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number37
DOIs
StatePublished - Sep 11 2015

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Glycogen
Metabolism
Knockout Mice
Muscle
Phosphates
Muscles
Phosphorylation
Lafora Disease
Degradation
Autophagy
Phosphoric Monoester Hydrolases
Neurodegenerative Diseases
Animals
Skeletal Muscle

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Muscle glycogen remodeling and glycogen phosphate metabolism following exhaustive exercise of wild type and laforin knockout mice. / Irimia, Jose M.; Tagliabracci, Vincent S.; Meyer, Catalina M.; Segvich, Dyann M.; De Paoli-Roach, Anna; Roach, Peter.

In: Journal of Biological Chemistry, Vol. 290, No. 37, 11.09.2015, p. 22686-22698.

Research output: Contribution to journalArticle

Irimia, Jose M. ; Tagliabracci, Vincent S. ; Meyer, Catalina M. ; Segvich, Dyann M. ; De Paoli-Roach, Anna ; Roach, Peter. / Muscle glycogen remodeling and glycogen phosphate metabolism following exhaustive exercise of wild type and laforin knockout mice. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 37. pp. 22686-22698.
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