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

W G Aschenbach; Y Suzuki; K Breeden; C Prats; M F Hirshman; S D Dufresne; K Sakamoto; P G Vilardo; M Steele; J H Kim; S L Jing; L J Goodyear; A A DePaoli-Roach

doi:10.1074/jbc.M105518200

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

W G Aschenbach, Y Suzuki, K Breeden, C Prats, M F Hirshman, S D Dufresne, K Sakamoto, P G Vilardo, M Steele, J H Kim, S L Jing, L J Goodyear, A A DePaoli-Roach

Endocrinology and Metabolism

93 Citations (Scopus)

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.-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 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 approximately 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/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.

Original language	English
Journal	Journal of Biological Chemistry
Volume	276
Issue number	43
Pages (from-to)	39959-67
Number of pages	8
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.M105518200
Publication status	Published - 2001

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Aschenbach, W. G., Suzuki, Y., Breeden, K., Prats, C., Hirshman, M. F., Dufresne, S. D., Sakamoto, K., Vilardo, P. G., Steele, M., Kim, J. H., Jing, S. L., Goodyear, L. J., & DePaoli-Roach, A. A. (2001). The muscle-specific protein phosphatase PP1G/R(GL)(G(M))is essential for activation of glycogen synthase by exercise. Journal of Biological Chemistry, 276(43), 39959-67. https://doi.org/10.1074/jbc.M105518200

Aschenbach, WG, Suzuki, Y, Breeden, K, Prats, C, Hirshman, MF, Dufresne, SD, Sakamoto, K, Vilardo, PG, Steele, M, Kim, JH, Jing, SL, Goodyear, LJ & DePaoli-Roach, AA 2001, 'The muscle-specific protein phosphatase PP1G/R(GL)(G(M))is essential for activation of glycogen synthase by exercise', Journal of Biological Chemistry, vol. 276, no. 43, pp. 39959-67. https://doi.org/10.1074/jbc.M105518200

@article{5b0da9a0b4d511df825b000ea68e967b,

title = "The muscle-specific protein phosphatase PP1G/R(GL)(G(M))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.-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 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 approximately 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/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.",

author = "Aschenbach, {W G} and Y Suzuki and K Breeden and C Prats and Hirshman, {M F} and Dufresne, {S D} and K Sakamoto and Vilardo, {P G} and M Steele and Kim, {J H} and Jing, {S L} and Goodyear, {L J} and DePaoli-Roach, {A A}",

note = "Keywords: Animals; Biological Transport; Carrier Proteins; Electric Stimulation; Enzyme Activation; Exercise Tolerance; Glucose; Glycogen; Glycogen Phosphorylase; Glycogen Synthase; Mice; Mice, Mutant Strains; Motor Activity; Muscle Contraction; Muscle, Skeletal; Phosphoprotein Phosphatases; Physical Conditioning, Animal; Physical Exertion; Protein Phosphatase 1",

year = "2001",

doi = "10.1074/jbc.M105518200",

language = "English",

volume = "276",

pages = "39959--67",

journal = "Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

number = "43",

}

TY - JOUR

T1 - The muscle-specific protein phosphatase PP1G/R(GL)(G(M))is essential for activation of glycogen synthase by exercise

AU - Aschenbach, W G

AU - Suzuki, Y

AU - Breeden, K

AU - Prats, C

AU - Hirshman, M F

AU - Dufresne, S D

AU - Sakamoto, K

AU - Vilardo, P G

AU - Steele, M

AU - Kim, J H

AU - Jing, S L

AU - Goodyear, L J

AU - DePaoli-Roach, A A

N1 - Keywords: Animals; Biological Transport; Carrier Proteins; Electric Stimulation; Enzyme Activation; Exercise Tolerance; Glucose; Glycogen; Glycogen Phosphorylase; Glycogen Synthase; Mice; Mice, Mutant Strains; Motor Activity; Muscle Contraction; Muscle, Skeletal; Phosphoprotein Phosphatases; Physical Conditioning, Animal; Physical Exertion; Protein Phosphatase 1

PY - 2001

Y1 - 2001

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). 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.-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 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 approximately 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/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.

AB - 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.-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 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 approximately 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/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.

U2 - 10.1074/jbc.M105518200

DO - 10.1074/jbc.M105518200

M3 - Journal article

C2 - 11522787

SN - 0021-9258

VL - 276

SP - 39959

EP - 39967

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 43

ER -

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

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