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.