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

William G. Aschenbach, Yoichi Suzuki, Kristine Breeden, Clara Prats, Michael F. Hirshman, Scott D. Dufresne, Kei Sakamoto, Pier Giuseppe Vilardo, Marcella Steele, Jong Hwa Kim, Shao Liang Jing, Laurie J. Goodyear, Anna De Paoli-Roach

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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). PPIG/R GL(GM) 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.-H., Vilardo, P. G., Zhang, H., Jie Yang, J., Cooper, L. D., Steele, M., Kennedy, A., Bock, C., Scrimgeour, A., Lawrence, J. C. Jr., L., and DePaoli-Roach, A. A. (2001) Mol. Cell. Biol. 21, 2683-2694) that insulin activates GS in muscle of RGL(GM) knockout (KO) mice similarly to the wild type (WT). To determine whether PP1G is involved in glycogen metabolism during muscle contractions, RGL 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 RGL OE mice are characterized by enhanced GS activity ratio and an ∼3-4-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/RGL 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 RGL KO mice, despite the normal insulin activation of GS.

Original languageEnglish
Pages (from-to)39959-39967
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number43
DOIs
StatePublished - Oct 26 2001

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Glycogen Synthase
Muscle Proteins
Phosphoprotein Phosphatases
Glycogen
Muscle
Chemical activation
Knockout Mice
Insulin
Metabolism
Muscle Contraction
Glucose
Skeletal Muscle
Basal Metabolism
Muscles
Exercise equipment
Sarcoplasmic Reticulum
Phosphoric Monoester Hydrolases
Running
Electric Stimulation
Animals

ASJC Scopus subject areas

  • Biochemistry

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The Muscle-specific Protein Phosphatase PP1G/RGL(GM) Is Essential for Activation of Glycogen Synthase by Exercise. / Aschenbach, William G.; Suzuki, Yoichi; Breeden, Kristine; Prats, Clara; Hirshman, Michael F.; Dufresne, Scott D.; Sakamoto, Kei; Vilardo, Pier Giuseppe; Steele, Marcella; Kim, Jong Hwa; Jing, Shao Liang; Goodyear, Laurie J.; De Paoli-Roach, Anna.

In: Journal of Biological Chemistry, Vol. 276, No. 43, 26.10.2001, p. 39959-39967.

Research output: Contribution to journalArticle

Aschenbach, WG, Suzuki, Y, Breeden, K, Prats, C, Hirshman, MF, Dufresne, SD, Sakamoto, K, Vilardo, PG, Steele, M, Kim, JH, Jing, SL, Goodyear, LJ & De Paoli-Roach, A 2001, 'The Muscle-specific Protein Phosphatase PP1G/RGL(GM) Is Essential for Activation of Glycogen Synthase by Exercise', Journal of Biological Chemistry, vol. 276, no. 43, pp. 39959-39967. https://doi.org/10.1074/jbc.M105518200
Aschenbach, William G. ; Suzuki, Yoichi ; Breeden, Kristine ; Prats, Clara ; Hirshman, Michael F. ; Dufresne, Scott D. ; Sakamoto, Kei ; Vilardo, Pier Giuseppe ; Steele, Marcella ; Kim, Jong Hwa ; Jing, Shao Liang ; Goodyear, Laurie J. ; De Paoli-Roach, Anna. / The Muscle-specific Protein Phosphatase PP1G/RGL(GM) Is Essential for Activation of Glycogen Synthase by Exercise. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 43. pp. 39959-39967.
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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). PPIG/R GL(GM) 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.-H., Vilardo, P. G., Zhang, H., Jie Yang, J., Cooper, L. D., Steele, M., Kennedy, A., Bock, C., Scrimgeour, A., Lawrence, J. C. Jr., L., and DePaoli-Roach, A. A. (2001) Mol. Cell. Biol. 21, 2683-2694) that insulin activates GS in muscle of RGL(GM) knockout (KO) mice similarly to the wild type (WT). To determine whether PP1G is involved in glycogen metabolism during muscle contractions, RGL 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 RGL OE mice are characterized by enhanced GS activity ratio and an ∼3-4-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/RGL 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 RGL KO mice, despite the normal insulin activation of GS.",
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AU - Prats, Clara

AU - Hirshman, Michael F.

AU - Dufresne, Scott D.

AU - Sakamoto, Kei

AU - Vilardo, Pier Giuseppe

AU - Steele, Marcella

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AU - Goodyear, Laurie J.

AU - De Paoli-Roach, Anna

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N2 - 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). PPIG/R GL(GM) 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.-H., Vilardo, P. G., Zhang, H., Jie Yang, J., Cooper, L. D., Steele, M., Kennedy, A., Bock, C., Scrimgeour, A., Lawrence, J. C. Jr., L., and DePaoli-Roach, A. A. (2001) Mol. Cell. Biol. 21, 2683-2694) that insulin activates GS in muscle of RGL(GM) knockout (KO) mice similarly to the wild type (WT). To determine whether PP1G is involved in glycogen metabolism during muscle contractions, RGL 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 RGL OE mice are characterized by enhanced GS activity ratio and an ∼3-4-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/RGL 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 RGL KO mice, despite the normal insulin activation of GS.

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