title: Muscle glycogen remodeling and glycogen phosphate metabolism following exhaustive exercise of wild type and laforin knockout mice.
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 glycogen-like 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 knock-out 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 knock-out 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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Irimia
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Tagliabracci
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Catalina M
authors.initials: CM
authors.lastname: Meyer
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Dyann M
authors.initials: DM
authors.lastname: Segvich
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Anna A
authors.initials: AA
authors.lastname: DePaoli-Roach
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202 proach@iu.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Roach
mesh_terms: D000818:Animals; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000235:genetics / Q000378:metabolism*; D020192:Lafora Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D010805:Physical Conditioning, Animal; D054558:Protein Tyrosine Phosphatases, Non-Receptor
chemical_list: D006003:Glycogen; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor
keywords: Lafora disease (Lafora progressive myoclonic epilepsy, MELF); branching; exercise; glycogen; laforin; phosphorylation