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 A Depaoli-Roach,Peter J Roach

doi:10.1074/jbc.m115.673897

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.

Highlights

Glycogen contains a low level of covalent phosphate that is significantly increased in Lafora disease
Effects of Exercise/Recovery on Glycogen Phosphorylation and Branching—To study the metabolism of the covalent phosphate in skeletal muscle glycogen in vivo, 3-month-old C57Bl/6J mice were exercised to exhaustion on a treadmill to deplete the polysaccharide and administered an oral bolus of glucose and allowed free access to food (Fig. 1)
The goal of the present study was to explore the dynamics of glycogen phosphorylation in mouse skeletal muscle, using exhaustive exercise as a means to deplete glycogen, and to monitor its synthesis after exercise

Summary

Introduction

Glycogen contains a low level of covalent phosphate that is significantly increased in Lafora disease. Results: Exercise removes phosphate from muscle glycogen, but not in a Lafora disease mouse model. Exercise of 3-month-old laforin knockout mice caused a similar depletion of glycogen but no loss of glycogen phosphate. 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

Objectives

Results

Conclusion