FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2150470419> ?p ?o ?g. }

• W2150470419 endingPage "39967" @default.
• W2150470419 startingPage "39959" @default.
• W2150470419 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/RGL(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 situelectrical 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. 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/RGL(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 situelectrical 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. glycogen synthase glycogen phosphorylase glycogen-associated type 1 serine/threonine protein phosphatase catalytic subunit of PP1 regulatory subunit of glycogen-associated PP1 protein targeting to glycogen glycogen synthase kinase-3 AMP-activated protein kinase knockout overexpressors extensor digitorum longus glucose 6-phosphate muscle creatine kinase wild type mitogen-activated protein phosphatidylinositol 3-kinase Insulin and contractile activity are major regulators of glycogen metabolism in skeletal muscle. Insulin stimulates glycogen synthesis, and postprandially, ∼80% of ingested glucose is taken up by skeletal muscle and converted to glycogen (1Jue T. Rothman D.L. Tavitian B.A. Shulman R.G. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1439-1442Crossref PubMed Scopus (81) Google Scholar, 2Shulman G.I. Rothman D.L. Jue T. Stein P. DeFronzo R.A. Shulman R.G. N. Engl. J. Med. 1990; 322: 223-228Crossref PubMed Scopus (1032) Google Scholar). Under these conditions, insulin activates glycogen synthase (GS),1 as well as glucose transport, via translocation of the GLUT4 transporter (3Lawrence Jr., J.C. Roach P.J. Diabetes. 1997; 46: 541-547Crossref PubMed Google Scholar, 4Azpiazu I. Manchester J. Skurat A.V. Roach P.J. Lawrence Jr., J.C. Am. J. Physiol. 2000; 278: E234-E243Crossref PubMed Google Scholar). Glycogen is a major fuel for the contractile activity of skeletal muscle. During contraction, glycogen is utilized as a source of energy, and it has been demonstrated that, perhaps paradoxically, glycogen resynthesis occurs while glycogen is being broken down (5Price T.B. Rothman D.L. Shulman R.G. Proc. Nutr. Soc. 1999; 58: 851-859Crossref PubMed Scopus (22) Google Scholar, 6Price T.B. Taylor R. Mason G.F. Rothman D.L. Shulman G.I. Shulman R.G. Med. Sci. Sports Exercise. 1994; 26: 983-991Crossref PubMed Scopus (39) Google Scholar). Presumably, this represents a mechanism for the rapid replenishment of glycogen stores when exercise ceases (7Bloch G. Chase J.R. Meyer D.B. Avison M.J. Shulman G.I. Shulman R.G. Am. J. Physiol. 1994; 266: E85-E91PubMed Google Scholar, 8Ivy J.L. Kuo C.H. Acta Physiol. Scand. 1998; 162: 295-304Crossref PubMed Scopus (90) Google Scholar). Contraction also promotes glucose uptake but most likely via a mechanism distinct from that triggered by insulin (9Lund S. Holman G.D. Schmitz O. Pedersen O. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5817-5821Crossref PubMed Scopus (409) Google Scholar, 10Yeh J.I. Gulve E.A. Rameh L. Birnbaum M.J. J. Biol. Chem. 1995; 270: 2107-2111Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, 11Lee A.D. Hansen P.A. Holloszy J.O. FEBS Lett. 1995; 361: 51-54Crossref PubMed Scopus (197) Google Scholar, 12Cushman S.W. Goodyear L.J. Pilch P.F. Ralston E. Galbo H. Ploug T. Kristiansen S. Klip A. Adv. Exp. Med. Biol. 1998; 441: 63-71Crossref PubMed Scopus (39) Google Scholar). Insulin-stimulated glucose uptake is blocked by the phosphatidylinositol 3-kinase (PI-3K) inhibitor, wortmannin. In contrast, the increased glucose uptake induced by exercise is wortmannin-insensitive, and the AMP-activated protein kinase (AMPK) (13Winder W.W. Hardie D.G. Am. J. Physiol. 1999; 277: E1-E10PubMed Google Scholar, 14Goodyear L.J. Exercise Sport Sci. Rev. 2000; 28: 113-116PubMed Google Scholar) has been postulated to play an important role. The period following exercise is characterized by increased glucose uptake and net glycogen synthesis in skeletal muscle, a scenario similar to insulin stimulation of muscle. Despite the fact that the mechanism of GS activation in response to insulin has been extensively studied, the molecular details of both insulin and contraction-induced activation remain mostly unknown.Glycogen metabolism is controlled largely by the coordinated action of the two enzymes GS and glycogen phosphorylase (Ph). Both enzymes are controlled by covalent phosphorylation and by allosteric effectors (15Cohen P. Boyer P. Krebs E.G. The Enzymes. 3rd Ed. Academic Press, Orlando1986: 461-497Google Scholar, 16Roach P.J. J. Biol. Chem. 1991; 266: 14139-14142Abstract Full Text PDF PubMed Google Scholar, 17Roach P.J. Skurat A.V. Harris R.A. Jefferson L.S. Cherrington A.D. Handbook of Physiology: The Endocrine Pancreas and Regulation of Metabolism. Oxford University Press, New York2001: 609-647Google Scholar). GS undergoes a complex multisite phosphorylation at nine sites by several protein kinases (17Roach P.J. Skurat A.V. Harris R.A. Jefferson L.S. Cherrington A.D. Handbook of Physiology: The Endocrine Pancreas and Regulation of Metabolism. Oxford University Press, New York2001: 609-647Google Scholar), most notably cAMP-dependent protein kinase, casein kinase I, casein kinase II, GSK-3, and AMPK (18Carling D. Hardie D.G. Biochim. Biophys. Acta. 1989; 1012: 81-86Crossref PubMed Scopus (254) Google Scholar) which generally lead to inactivation. Important regulatory phosphorylation sites are distributed between the NH2 (sites 2 and 2a) and the COOH termini (sites 3a and 3b) of the GS molecule (19Lawrence Jr., J.C. Hiken J.F. DePaoli-Roach A.A. Roach P.J. J. Biol. Chem. 1983; 258: 10710-10719Abstract Full Text PDF PubMed Google Scholar, 20Skurat A.V. Wang Y. Roach P.J. J. Biol. Chem. 1994; 269: 25534-25542Abstract Full Text PDF PubMed Google Scholar, 21Skurat A.V. Dietrich A.D. Roach P.J. Diabetes. 2000; 49: 1096-1100Crossref PubMed Scopus (56) Google Scholar). Full activity can be restored to phosphorylated enzyme by the presence of the allosteric activator glucose-6-P (G-6P). Ph is activated by phosphorylation of a single site by phosphorylase kinase (22Cohen P. Biochem. Soc. Trans. 1987; 15: 999-1001Crossref PubMed Scopus (8) Google Scholar). The less active, dephosphorylated form (Ph b) acquires full activity in the presence of the allosteric effector AMP. Dephosphorylation of all three of these key regulatory proteins, GS, Ph, and phosphorylase kinase, is believed to be catalyzed primarily by glycogen-associated phosphatases (PP1Gs) (23Hubbard M.J. Cohen P. Eur. J. Biochem. 1989; 180: 457-465Crossref PubMed Scopus (59) Google Scholar).The three forms of PP1G present in skeletal muscle consist of a catalytic subunit, PP1c, in association with a glycogen-targeting subunit, PTG, R6, or RGL (also called GM(24Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Diabetes. 2000; 49: 1967-1977Crossref PubMed Scopus (147) Google Scholar, 25Printen J.A. Brady M.J. Saltiel A.R. Science. 1997; 275: 1475-1478Crossref PubMed Scopus (240) Google Scholar, 26Armstrong C.G. Browne G.J. Cohen P. Cohen P.T. FEBS Lett. 1997; 418: 210-214Crossref PubMed Scopus (85) Google Scholar, 27Stralfors P. Hiraga A. Cohen P. Eur. J. Biochem. 1985; 149: 295-303Crossref PubMed Scopus (198) Google Scholar, 28Tang P.M. Bondor J.A. Swiderek K.M. DePaoli-Roach A.A. J. Biol. Chem. 1991; 266: 15782-15789Abstract Full Text PDF PubMed Google Scholar)). RGL is striated muscle specific, whereas the other two subunits are more ubiquitously distributed. PTG may interact with glycogen-metabolizing enzymes (29Fong N.M. Jensen T.C. Shah A.S. Parekh N.N. Saltiel A.R. Brady M.J. J. Biol. Chem. 2000; 275: 35034-35039Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar) and has been implicated in insulin control of glycogen metabolism (25Printen J.A. Brady M.J. Saltiel A.R. Science. 1997; 275: 1475-1478Crossref PubMed Scopus (240) Google Scholar, 30Gasa R. Jensen P.B. Berman H.K. Brady M.J. DePaoli-Roach A.A. Newgard C.B. J. Biol. Chem. 2000; 275: 26396-26403Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Adenovirus-mediated overexpression of PTG in cultured human muscle cells results in glycogen accumulation and activation of GS (31Lerin C. Montell E. Berman H.K. Newgard C.B. Gomez-Foix A.M. J. Biol. Chem. 2000; 275: 39991-39995Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). However, the mechanism(s) of regulation of PTG and R6-associated phosphatases are completely unknown.The muscle-specific phosphatase PP1G/RGL, composed of PP1c associated with RGL (GM), dephosphorylates the regulatory sites on GS as well as on Ph and phosphorylase kinase (23Hubbard M.J. Cohen P. Eur. J. Biochem. 1989; 180: 457-465Crossref PubMed Scopus (59) Google Scholar,27Stralfors P. Hiraga A. Cohen P. Eur. J. Biochem. 1985; 149: 295-303Crossref PubMed Scopus (198) Google Scholar). Phosphatase activity was thought to be regulated hormonally by phosphorylation of site 1 (Ser48) and site 2 (Ser67) on the RGL subunit (32Dent P. Lavoinne A. Nakielny S. Caudwell F.B. Watt P. Cohen P. Nature. 1990; 348: 302-308Crossref PubMed Scopus (402) Google Scholar, 33Nakielny S. Campbell D.G. Cohen P. Eur. J. Biochem. 1991; 199: 713-722Crossref PubMed Scopus (69) Google Scholar). Phosphorylation of site 1 by the insulin-stimulated protein kinase p90Rsk would enhance association of PP1c to RGLand therefore activity toward GS and phosphorylase kinase (32Dent P. Lavoinne A. Nakielny S. Caudwell F.B. Watt P. Cohen P. Nature. 1990; 348: 302-308Crossref PubMed Scopus (402) Google Scholar). Conversely, phosphorylation of site 2 would cause dissociation of PP1c and greatly reduced activity (33Nakielny S. Campbell D.G. Cohen P. Eur. J. Biochem. 1991; 199: 713-722Crossref PubMed Scopus (69) Google Scholar). However, work from several laboratories (34Robinson L.J. Razzack Z.F. Lawrence Jr., J.C. James D.E. J. Biol. Chem. 1993; 268: 26422-26427Abstract Full Text PDF PubMed Google Scholar, 35Azpiazu I. Saltiel A.R. DePaoli-Roach A.A. Lawrence J.C. J. Biol. Chem. 1996; 271: 5033-5039Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 36Lazar D.F. Wiese R.J. Brady M.J. Mastick C.C. Waters S.B. Yamauchi K. Pessin J.E. Cuatrecasas P. Saltiel A.R. J. Biol. Chem. 1995; 270: 20801-20807Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar, 37Dufresne S.D. Bjorbaek C. El-Haschimi K. Zhao Y. Aschenbach W.G. Moller D.E. Goodyear L.J. Mol. Cell. Biol. 2001; 21: 81-87Crossref PubMed Scopus (105) Google Scholar) has demonstrated that insulin control of glycogen metabolism does not involve the mitogen-activated protein (MAP) kinase pathway. These studies did not exclude the possibility that insulin could activate PP1G/RGL via other pathways. Our recent observations (38Suzuki 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. DePaoli-Roach A.A. Mol. Cell. Biol. 2001; 21: 2683-2694Crossref PubMed Scopus (129) Google Scholar) showed that RGL null mice have significant reductions in basal GS −/+ G-6P activity ratio and total activity and muscle glycogen content. However, RGL KO and wild type mice exhibited a similar 2-fold activation of GS in skeletal muscle in response to insulin stimulation. These studies clearly demonstrate that PP1G/RGL is not essential for the hormonal control. Instead a novel GS-specific insulin-stimulated type 1 phosphatase was detected (38Suzuki 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. DePaoli-Roach A.A. Mol. Cell. Biol. 2001; 21: 2683-2694Crossref PubMed Scopus (129) Google Scholar), indicating that a distinct phosphatase form may be involved. A large body of evidence suggests that insulin activation of GS proceeds via the PI-3K/Akt pathway that leads to phosphorylation and inhibition of GSK-3 (39Shepherd P.R. Nave B.T. Siddle K. Biochem. J. 1995; 305: 25-28Crossref PubMed Scopus (230) Google Scholar, 40Cross D.A. Alessi D.R. Cohen P. Andjelkovich M. Hemmings B.A. Nature. 1995; 378: 785-789Crossref PubMed Scopus (4318) Google Scholar, 41Welsh G.I. Proud C.G. Biochem. J. 1993; 294: 625-629Crossref PubMed Scopus (350) Google Scholar). However, GSK-3 alone is not sufficient to account for GS dephosphorylation and activation by insulin (3Lawrence Jr., J.C. Roach P.J. Diabetes. 1997; 46: 541-547Crossref PubMed Google Scholar, 20Skurat A.V. Wang Y. Roach P.J. J. Biol. Chem. 1994; 269: 25534-25542Abstract Full Text PDF PubMed Google Scholar, 21Skurat A.V. Dietrich A.D. Roach P.J. Diabetes. 2000; 49: 1096-1100Crossref PubMed Scopus (56) Google Scholar). The mTOR, mammalian target for the immunosuppressant drug rapamycin, pathway is also activated by insulin. Rapamycin has been shown to block insulin-mediated activation of GS in muscle and 3T3-L1 adipocytes (35Azpiazu I. Saltiel A.R. DePaoli-Roach A.A. Lawrence J.C. J. Biol. Chem. 1996; 271: 5033-5039Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 39Shepherd P.R. Nave B.T. Siddle K. Biochem. J. 1995; 305: 25-28Crossref PubMed Scopus (230) Google Scholar) without affecting insulin-induced inactivation of GSK-3 (42Cross D.A. Watt P.W. Shaw M. van der Kaay J. Downes C.P. Holder J.C. Cohen P. FEBS Lett. 1997; 406: 211-215Crossref PubMed Scopus (190) Google Scholar), opening the possibility that mTOR could control GS phosphorylation via a phosphatase. Therefore, insulin may promote glycogen synthesis both via inhibition of GSK-3 andstimulation of a type 1 phosphatase.Even though PP1G/RGL is not required for insulin-stimulated glycogen synthesis in skeletal muscle, it may be a component of the response to contractile activity. GS has been shown to be regulated differentially in skeletal muscle by insulin and contractions duringin vitro and in vivo studies (43Franch J. Aslesen R. Jensen J. Biochem. J. 1999; 344: 231-235Crossref PubMed Scopus (44) Google Scholar, 44O'Gorman D.J. Del Aguila L.F. Williamson D.L. Krishnan R.K. Kirwan J.P. J. Appl. Physiol. 2000; 89: 1412-1419Crossref PubMed Scopus (22) Google Scholar, 45Markuns J.F. Wojtaszewski J.F. Goodyear L.J. J. Biol. Chem. 1999; 274: 24896-24900Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar), with contractions and exercise resulting in a prolonged, substantially greater activation compared with maximal insulin treatment. This suggests that contractions may utilize a separate signaling pathway from insulin to activate GS in response to contractions. Changes in GS activity in human muscle biopsy samples obtained during isometric contractions are associated with changes in protein phosphatase activity (46Katz A. Raz I. Pfluegers Arch. Eur. J. Physiol. 1995; 431: 259-265Crossref PubMed Scopus (15) Google Scholar), but the identity of this enzyme has not been determined. The purpose of the present study was to examine whether the low skeletal muscle glycogen content in RGL KO mice would lead to impaired exercise capacity and to investigate the role of PP1G/RGL in glycogen metabolism during muscle contraction. Our approach was to use two different models of exercise: in vivo treadmill running and in situ muscle contraction in mice that either overexpress or are deficient in the RGLsubunit. We demonstrate that GS activation is abolished in RGL KO mice during both in vivo and in situ models of exercise. This finding provides compelling evidence that PP1G/RGL is essential for activation of GS during exercise and may provide a mechanism to explain the reduced muscle glycogen content despite the normal insulin control of GS in the KO mice.DISCUSSIONThe major finding of the current investigation is that the marked increase in GS activity in skeletal muscle in response to both in vivo exercise and in situ electrically induced contraction is abolished in mice lacking the RGL, regulatory/glycogen-targeting subunit of PP1G. In exercised WT mice, the changes in GS activity state are accompanied by increased electrophoretic mobility of the protein, diagnostic of dephosphorylation. To date, the mechanism by which GS is activated during muscle contractions has not been elucidated. It is well known that the rate of glucose uptake is greatly increased in contracting skeletal muscle, which is associated with an accumulation of G-6P within the myoplasm (7Bloch G. Chase J.R. Meyer D.B. Avison M.J. Shulman G.I. Shulman R.G. Am. J. Physiol. 1994; 266: E85-E91PubMed Google Scholar). Increased G-6P concentration may provide a mechanism for regulating GS during exercise via its allosteric effect on activity and also by rendering GS more susceptible to dephosphorylation by phosphatases (55Villar-Palasi C. Guinovart J.J. FASEB J. 1997; 11: 544-558Crossref PubMed Scopus (158) Google Scholar). However, GS was not activated in RGL KO mice despite the normal rates of basal and post-contraction glucose uptake compared with WT mice, suggesting that RGL mediates some other mechanism by which contraction induces GS activation. Decreased phosphorylation of GS could be due to decreased kinase activity, increased phosphatase activity, or both. Changes in GS activity in skeletal muscle biopsies from exercising humans have been associated with changes in the activity of a GS phosphatase (46Katz A. Raz I. Pfluegers Arch. Eur. J. Physiol. 1995; 431: 259-265Crossref PubMed Scopus (15) Google Scholar). However, these studies were correlative, and the enzyme form was not identified. The results of the in vivoand in situ experiments with RGL KO mice provide the first direct evidence that PP1G/RGL is a phosphatase involved in the signaling cascade leading to activation of glycogen synthase during exercise and additionally demonstrate that it is an essential component of this control.PP1G/RGL was originally proposed to mediate insulin-stimulated glycogen synthesis in skeletal muscle via the MAP kinase signaling pathway (32Dent P. Lavoinne A. Nakielny S. Caudwell F.B. Watt P. Cohen P. Nature. 1990; 348: 302-308Crossref PubMed Scopus (402) Google Scholar). Although subsequent studies using epidermal growth factor (35Azpiazu I. Saltiel A.R. DePaoli-Roach A.A. Lawrence J.C. J. Biol. Chem. 1996; 271: 5033-5039Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar), MAP kinase/extracellular signal-regulated kinase kinase inhibitors (36Lazar D.F. Wiese R.J. Brady M.J. Mastick C.C. Waters S.B. Yamauchi K. Pessin J.E. Cuatrecasas P. Saltiel A.R. J. Biol. Chem. 1995; 270: 20801-20807Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar), and RSK2 KO mice (37Dufresne S.D. Bjorbaek C. El-Haschimi K. Zhao Y. Aschenbach W.G. Moller D.E. Goodyear L.J. Mol. Cell. Biol. 2001; 21: 81-87Crossref PubMed Scopus (105) Google Scholar) argued against an involvement of the MAP kinase signaling cascade, they did not exclude the possibility that PP1G/RGL mediated the insulin response. However, recent work (38Suzuki 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. DePaoli-Roach A.A. Mol. Cell. Biol. 2001; 21: 2683-2694Crossref PubMed Scopus (129) Google Scholar) demonstrating normal activation of GS by insulin in RGL KO mice clearly showed that PP1G/RGL is not required. Furthermore, although insulin may increase phosphorylation of RGL at Ser48 and Ser67 in cultured cell systems (56Liu J. Brautigan D.L. J. Biol. Chem. 2000; 275: 15940-15947Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar), it does not affect phosphorylation at these sites in vivo either in rat (57Walker K.S. Watt P.W. Cohen P. FEBS Lett. 2000; 466: 121-124Crossref PubMed Scopus (46) Google Scholar) or mouse (38Suzuki 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. DePaoli-Roach A.A. Mol. Cell. Biol. 2001; 21: 2683-2694Crossref PubMed Scopus (129) Google Scholar) skeletal muscle. Activation of GS by PP1G/RGLduring muscle contraction appears to be a mechanism that is not shared with the insulin signaling pathway, and insulin stimulation of GS appears to involve a distinct phosphatase specific for GS (38Suzuki 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. DePaoli-Roach A.A. Mol. Cell. Biol. 2001; 21: 2683-2694Crossref PubMed Scopus (129) Google Scholar). A large body of evidence suggests that insulin and exercise control glucose uptake by distinct mechanisms, mediated by IP-3K/Akt and AMPK, respectively. Therefore, in a similar way, insulin and contraction may stimulate GS through activation of different protein phosphatases. Whether RGL is a downstream effector of AMPK is an interesting question that is currently under investigation. However, other pathways, such as elevation of intracellular Ca2+concentration, cannot be excluded. It is unlikely that RGL is controlled by the MAP kinase pathway, since the MAP kinase kinase inhibitor PD98059 did not alter contraction-induced increases in muscle glycogen synthase activity (58Hayashi T. Hirshman M.F. Dufresne S.D. Goodyear L.J. Am. J. Physiol. 1999; 277: C701-C707Crossref PubMed Google Scholar).Although our data indicate that PP1G/RGL is an obligatory component of an exercise-activated signaling pathway that is not shared by insulin, we cannot exclude the involvement of other mechanisms to activate glycogen synthase during muscle contraction. Specific enzymes in such pathways could represent points of convergence between insulin and exercise signaling. For example, insulin activates a PI-3K/Akt-dependent pathway that inhibits GSK-3 (39Shepherd P.R. Nave B.T. Siddle K. Biochem. J. 1995; 305: 25-28Crossref PubMed Scopus (230) Google Scholar, 40Cross D.A. Alessi D.R. Cohen P. Andjelkovich M. Hemmings B.A. Nature. 1995; 378: 785-789Crossref PubMed Scopus (4318) Google Scholar, 41Welsh G.I. Proud C.G. Biochem. J. 1993; 294: 625-629Crossref PubMed Scopus (350) Google Scholar). We have previously shown (45Markuns J.F. Wojtaszewski J.F. Goodyear L.J. J. Biol. Chem. 1999; 274: 24896-24900Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar) that both GSK-3α and -β isoforms are inhibited in rat skeletal muscle during treadmill exercise. However, as for insulin signaling, GSK-3 alone cannot account for GS activation, since modulation of activity requires changes in the phosphorylation of NH2-terminal phosphorylation sites that are not substrates for GSK-3 (3Lawrence Jr., J.C. Roach P.J. Diabetes. 1997; 46: 541-547Crossref PubMed Google Scholar, 20Skurat A.V. Wang Y. Roach P.J. J. Biol. Chem. 1994; 269: 25534-25542Abstract Full Text PDF PubMed Google Scholar, 21Skurat A.V. Dietrich A.D. Roach P.J. Diabetes. 2000; 49: 1096-1100Crossref PubMed Scopus (56) Google Scholar). Also, GSK-3 expression is not altered in the RGL KO mice (38Suzuki 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. DePaoli-Roach A.A. Mol. Cell. Biol. 2001; 21: 2683-2694Crossref PubMed Scopus (129) Google Scholar). Nevertheless, it is possible that exercise-induced inhibition of GSK-3 plays an ancillary role in activating GS, in a pathway shared with insulin. Further work is required to identify what upstream effectors regulate PP1G/RGL and GSK-3 during muscle contractions.Both the RGL-overexpressing and KO mice exhibit differences in basal muscle glycogen concentrations compared with their respective wild type littermates. The RGL-overexpressing animals have significantly increased glycogen, whereas glycogen is severely depleted in the KO mice. Analysis of GS and Ph activities in muscle extracts indicates that these differences are due to alterations in the rates of both synthesis and degradation. Overexpression of related phosphatase-targeting proteins, such as PTG, has been shown to promote glycogen synthesis in hepatocytes in culture (30Gasa R. Jensen P.B. Berman H.K. Brady M.J. DePaoli-Roach A.A. Newgard C.B. J. Biol. Chem. 2000; 275: 26396-26403Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 59Berman H.K. O'Doherty R.M. Anderson P. Newgard C.B. J. Biol. Chem. 1998; 273: 26421-26425Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar) and in vivo (60O'Doherty R.M. Jensen P.B. Anderson P. Jones J.G. Berman H.K. Kearney D. Newgard C.B. J. Clin. Invest. 2000; 105: 479-488Crossref PubMed Scopus (68) Google Scholar) and in cultured human muscle cells (31Lerin C. Montell E. Berman H.K. Newgard C.B. Gomez-Foix A.M. J. Biol. Chem. 2000; 275: 39991-39995Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar), presumably by increasing phosphatase activity toward glycogen-bound substrates. Although a role for PTG in insulin control of glycogen metabolism has been proposed, our work indicates that PTG is not involved in regulation by contraction. Most importantly, the present study emphasizes the fact that the various forms of PP1G are not redundant since neither the PTG nor the R6 forms of PP1G complemented the inability of the RGL KO mice to activate GS in response to contraction. Also, the fact that RGL overexpression did not alter exercise performance or the ability to activate GS indicates that gene dosage is not a critical factor. Various reports (62Laurent D. Hundal R.S. Dresner A. Price T.B. Vogel S.M. Petersen K.F. Shulman G.I. Am. J. Physiol. 2000; 278: E663-E668Crossref PubMed Google Scholar, 63Price T.B. Laurent D. Petersen K.F. Rothman D.L. Shulman G.I. J. Appl. Physiol. 2000; 88: 698-704Crossref PubMed Scopus (37) Google Scholar, 64Kawanaka K. Nolte L.A. Han D.H. Hansen P.A. Holloszy J.O. Am. J. Physiol. 2000; 279: E1311-E1318Crossref PubMed Google Scholar, 65Derave W. Lund S. Holman G.D. Wojtaszewski J. Pedersen O. Richter E.A. Am. J. Physiol. 1999; 277: E1103-E1110PubMed Google Scholar) have argued that the intracellular glycogen content is inversely related to insulin- and exercise-induced stimulation of glucose transport and GS. However, in the RGL OE and KO animals, the muscle glycogen content ranged from ∼4-fold above normal to ∼5-fold lower, without any observed differences in glucose uptake, whether basal, contraction-induced, or insulin-induced (38Suzuki 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. DePaoli-Roach A.A. Mol. Cel" @default.
• W2150470419 created "2016-06-24" @default.
• W2150470419 creator A5003779033 @default.
• W2150470419 creator A5007530334 @default.
• W2150470419 creator A5012147587 @default.
• W2150470419 creator A5020560871 @default.
• W2150470419 creator A5020890107 @default.
• W2150470419 creator A5025477215 @default.
• W2150470419 creator A5032370478 @default.
• W2150470419 creator A5037049837 @default.
• W2150470419 creator A5039947894 @default.
• W2150470419 creator A5043051060 @default.
• W2150470419 creator A5060228222 @default.
• W2150470419 creator A5063273755 @default.
• W2150470419 creator A5080176195 @default.
• W2150470419 date "2001-10-01" @default.
• W2150470419 modified "2023-10-12" @default.
• W2150470419 title "The Muscle-specific Protein Phosphatase PP1G/RGL(GM) Is Essential for Activation of Glycogen Synthase by Exercise" @default.
• W2150470419 cites W127826371 @default.
• W2150470419 cites W1451690345 @default.
• W2150470419 cites W1525701947 @default.
• W2150470419 cites W1527579401 @default.
• W2150470419 cites W1531537331 @default.
• W2150470419 cites W1566749908 @default.
• W2150470419 cites W1580289363 @default.
• W2150470419 cites W1586737639 @default.
• W2150470419 cites W1599961357 @default.
• W2150470419 cites W1605839892 @default.
• W2150470419 cites W1859180667 @default.
• W2150470419 cites W1925113912 @default.
• W2150470419 cites W1943009833 @default.
• W2150470419 cites W1947575656 @default.
• W2150470419 cites W1963893245 @default.
• W2150470419 cites W1967458195 @default.
• W2150470419 cites W1975169876 @default.
• W2150470419 cites W1977182622 @default.
• W2150470419 cites W1986503768 @default.
• W2150470419 cites W1991250054 @default.
• W2150470419 cites W1993963200 @default.
• W2150470419 cites W2001866120 @default.
• W2150470419 cites W2018926746 @default.
• W2150470419 cites W2019691564 @default.
• W2150470419 cites W2024942502 @default.
• W2150470419 cites W2032083983 @default.
• W2150470419 cites W2035705837 @default.
• W2150470419 cites W2036601355 @default.
• W2150470419 cites W2036754434 @default.
• W2150470419 cites W203973011 @default.
• W2150470419 cites W2041199058 @default.
• W2150470419 cites W2058138221 @default.
• W2150470419 cites W2059226722 @default.
• W2150470419 cites W2062733425 @default.
• W2150470419 cites W2064164260 @default.
• W2150470419 cites W2066187263 @default.
• W2150470419 cites W2077789837 @default.
• W2150470419 cites W2079084102 @default.
• W2150470419 cites W2092774909 @default.
• W2150470419 cites W2092944469 @default.
• W2150470419 cites W2094625115 @default.
• W2150470419 cites W2094850798 @default.
• W2150470419 cites W2095512119 @default.
• W2150470419 cites W2106324494 @default.
• W2150470419 cites W2111371276 @default.
• W2150470419 cites W2114647345 @default.
• W2150470419 cites W2115988605 @default.
• W2150470419 cites W2140664543 @default.
• W2150470419 cites W2155653958 @default.
• W2150470419 cites W2157804459 @default.
• W2150470419 cites W2169250745 @default.
• W2150470419 cites W2173763762 @default.
• W2150470419 cites W2188137316 @default.
• W2150470419 cites W2341717561 @default.
• W2150470419 cites W2405705082 @default.
• W2150470419 cites W2801973984 @default.
• W2150470419 cites W4254937834 @default.
• W2150470419 cites W4293247451 @default.
• W2150470419 doi "https://doi.org/10.1074/jbc.m105518200" @default.
• W2150470419 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/11522787" @default.
• W2150470419 hasPublicationYear "2001" @default.
• W2150470419 type Work @default.
• W2150470419 sameAs 2150470419 @default.
• W2150470419 citedByCount "104" @default.
• W2150470419 countsByYear W21504704192012 @default.
• W2150470419 countsByYear W21504704192013 @default.
• W2150470419 countsByYear W21504704192014 @default.
• W2150470419 countsByYear W21504704192015 @default.
• W2150470419 countsByYear W21504704192016 @default.
• W2150470419 countsByYear W21504704192018 @default.
• W2150470419 countsByYear W21504704192019 @default.
• W2150470419 countsByYear W21504704192020 @default.
• W2150470419 countsByYear W21504704192021 @default.
• W2150470419 countsByYear W21504704192022 @default.
• W2150470419 crossrefType "journal-article" @default.
• W2150470419 hasAuthorship W2150470419A5003779033 @default.
• W2150470419 hasAuthorship W2150470419A5007530334 @default.
• W2150470419 hasAuthorship W2150470419A5012147587 @default.
• W2150470419 hasAuthorship W2150470419A5020560871 @default.
• W2150470419 hasAuthorship W2150470419A5020890107 @default.

• next