The Muscle-specific Protein Phosphatase PP1G/RGL(GM) Is Essential for Activation of Glycogen Synthase by Exercise

Abstract

In skeletal muscle both insulin and contractile activity are physiological stimuli for glycogen synthesis, which is thought to result in part from the dephosphorylation and activation of glycogen synthase (GS). PP1G/ R GL (G M ) is a glycogen/sarcoplasmic reticulum-associated type 1 phosphatase that was originally postulated to mediate insulin control of glycogen metabolism. However, we recently showed (Suzuki, Y., Lanner, C., Kim, J. Cell. Biol. 21, 2683-2694) that insulin activates GS in muscle of R GL (G M ) knockout (KO) mice similarly to the wild type (WT).To determine whether PP1G is involved in glycogen metabolism during muscle contractions, R GL KO and overexpressors (OE) were subjected to two models of contraction, in vivo treadmill running and in situ electrical stimulation. Both procedures resulted in a 2-fold increase in the GS ؊/؉ glucose-6-P activity ratio in WT mice, but this response was completely absent in the KO mice. The KO mice, which also have a reduced GS activity associated with significantly reduced basal glycogen levels, exhibited impaired maximal exercise capacity, but contraction-induced activation of glucose transport was unaffected. The R GL OE mice are characterized by enhanced GS activity ratio and an ϳ3-4-fold increase in glycogen content in skeletal muscle. These animals were able to tolerate exercise normally. Stimulation of GS and glucose uptake following muscle contraction was not significantly different as compared with WT littermates. These results indicate that although PP1G/R GL is not necessary for activation of GS by insulin, it is essential for regulation of glycogen metabolism under basal conditions and in response to contractile activity, and may explain the reduced muscle glycogen content in the R GL KO mice, despite the normal insulin activation of GS.

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

“…By inhibiting phosphorylation of mGS and R5/PTG, this would lead to net dephosphorylation and activation of mGS, thus ensuring that glycogen is rapidly replenished whenever it becomes depleted. This would help to explain the paradox that mGS is found to be dephosphorylated and activated following exercise (Aschenbach et al 2001), despite the fact that AMPK (which phosphorylates and inactivates mGS) is switched on during exercise (Winder and Hardie 1996). Our model suggests that the pool of AMPK bound to glycogen is regulated by the structural state of glycogen particles, a mechanism not available to other pools of AMPK.…”

The Experimental Type 2 Diabetes Therapy Glycogen Phosphorylase Inhibition Can Impair Aerobic Muscle Function During Prolonged Contraction

“…Furthermore, when glycogen synthase activity is genetically ablated (37), endurance exercise remains unchanged. In contrast, disruption of protein phosphatase PP1G/R GL (which activates glycogen synthase) reduces muscle glycogen content by 50% and function by Ͼ50% in an alternative background strain of mouse (40). As with all transgenic studies, evidence based on a single mutation with a single background strain can be challenging to interpret.…”

Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease

“…Binding to glycogen appears to stabilize GS. For example, overexpression of another type 1 phosphatase regulatory subunit, R GL /G M , leads to increased glycogen GS protein in muscle (51). Decreased glycogen levels, as in R GL knock-out (29) or PTG knock-out 3 animals, were associated with decreased GS.…”