The muscle-specific protein phosphatase PP1G/R-GL(G(M)) is essential for activation of glycogen synthase by exercise

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 I phosphatase that w as originally postulated to mediate insulin control of glycogen metabolism. However, we recently showed (Suzuki, Y., Lanner, C., Kim, J.-H., Vilardo, P. G., Zhang, H., Jie Yang, J., Cooper, L. D., Steele, M., Kennedy, A., Boc k, C., Scrimgeour, A., Lawrence, J. C. Jr., L., and DePaoli-Roach, A. A. (2 001) Mol. 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 determin e whether PP1G is involved in glycogen metabolism during muscle contraction s, RGL KO and overexpressors (OE) were subjected to two models of contracti on, in vivo treadmill running and in situ electrical stimulation. Both proc edures resulted in a 2-fold increase in the GS -/+ glucose-6-P activity rat io 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 significantl y reduced basal glycogen levels, exhibited impaired maximal exercise capaci ty, but contraction-induced activation of glucose transport was unaffected. The R-GL OE mice are characterized by enhanced GS activity ratio and an si milar to3-4-fold increase in glycogen content in skeletal muscle. These ani mals were able to tolerate exercise normally. Stimulation of GS and glucose uptake following muscle contraction was not significantly different as com pared with WT littermates. These results indicate that although PP1G/R-GL i s not necessary for activation of GS by insulin, it is essential for regula tion of glycogen metabolism under basal conditions and in response to contr actile activity, and may explain the reduced muscle glycogen content in the R-GL KO mice, despite the normal insulin activation of GS.