Regulation of glycogen synthase and phosphorylase during recovery from high-intensity exercise in the rat

Bräu, Lambert; Ferreira, Luis D.; Nikolovski, S.; Raja, Ghazala Kaukab; Palmer, T.N.; Fournier, Paul A.

doi:10.1042/bj3220303

Cited by 41 publications

(66 citation statements)

References 57 publications

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“…In muscle, GS is thought to be activated by glycogen depletion (12)(13)(14)(15), via release of an inhibitory effect of glycogen on PP1 (16), and by transient increments in glucose-6-P resulting from insulin and glucose stimulation (26). The current study demonstrates that these modes of regulation of GS activity are not required for activation of glycogen synthesis in muscle in response to PTG overexpression.…”

Section: Discussionmentioning

confidence: 67%

“…This effect has been ascribed to the activation of GS triggered by exhaustion of glycogen stores (12)(13)(14)(15), mediated in turn by release of the inhibitory action of glycogen on PP1 (16). Additionally, at elevated glycogen levels, it has been suggested that glucose-6-P plays an important regulatory role by binding to GS and rendering it a better substrate for protein phosphatases 1 and 2A (17).…”

mentioning

confidence: 99%

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Overexpression of Protein Targeting to Glycogen in Cultured Human Muscle Cells Stimulates Glycogen Synthesis Independent of Glycogen and Glucose 6-Phosphate Levels

Lerín

Montell

Berman

et al. 2000

Journal of Biological Chemistry

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There is growing evidence that glycogen targeting subunits of protein phosphatase-1 play a critical role in regulation of glycogen metabolism. In the current study, we have investigated the effects of adenovirus-mediated overexpression of a specific glycogen targeting subunit known as protein targeting to glycogen (PTG) in cultured human muscle cells. PTG was overexpressed both in muscle cells cultured at high glucose (glycogen replete) or in cells incubated for 18 h in the absence of glucose and then incubated in high glucose (glycogen re-synthesizing). In both glycogen replete and glycogen resynthesizing cells, PTG overexpression caused glycogen to be synthesized at a linear rate 1-5 days after viral treatment, while in cells treated with a virus lacking a cDNA insert (control virus), glycogen content reached a plateau at day 1 with no further increase. In the glycogen replete PTG overexpressing cells, glycogen content was 20 times that in controls at day 5. Furthermore, in cells undergoing glycogen resynthesis, PTG overexpression caused a doubling of the initial rate of glycogen synthesis over the first 24 h relative to cells treated with control virus. In both sets of experiments, the effects of PTG on glycogen synthesis were correlated with a 2-3-fold increase in glycogen synthase activity state, with no changes in glycogen phosphorylase activity. The alterations in glycogen synthase activity were not accompanied by changes in the intracellular concentration of glucose 6-phosphate. We conclude that PTG overexpression activates glycogen synthesis in a glucose 6-phosphate-independent manner in human muscle cells while overriding glycogen-mediated inhibition. Our findings suggest that modulation of PTG expression in muscle may be a mechanism for enhancing muscle glucose disposal and improving glucose tolerance in diabetes.Glycogen metabolism is regulated in part by a balance between glycogen synthase (GS) 1 and glycogen phosphorylase (GP) activities. Both enzymes are known to be modified by phosphorylation-dephosphorylation reactions. Dephosphorylation of GS causes its activation, while GP becomes inactivated. Dephosphorylation of glycogen metabolizing enzymes has been mainly attributed to protein phosphatase 1 (PP1) activity (1). In support of this notion, PP1 is known to bind to the glycogen particle in muscle, and has also been shown to catalyze dephosphorylation of GS, GP, and phosphorylase kinase when assayed in vitro (2). However, less is known about the mechanisms that control the specific action of PP1 on glycogen metabolizing enzymes in the intact cell.It is increasingly appreciated that the activity of PP1 is affected by proteins that bind to the enzyme and target it to specific intracellular sites. With regard to glycogen metabolism, a family of glycogen targeting subunits of PP1 have recently emerged. These proteins include G M or R Gl (3) which is expressed in skeletal muscle, G L (4), expressed mainly in the liver, and PPP1R5 or protein targeting to glycogen (PTG) (5, 6) and PPP1R6 (7), which are...

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Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

Overexpression of Protein Targeting to Glycogen in Cultured Human Muscle Cells Stimulates Glycogen Synthesis Independent of Glycogen and Glucose 6-Phosphate Levels

Lerín

Montell

Berman

et al. 2000

Journal of Biological Chemistry

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“…27). Glycogen depletion in skeletal muscle caused by intense bouts of exercise has been shown to result in transient increases in both basal glucose uptake and glycogen synthase activity (49,50). Additionally, the sensitivity of glycogen-depleted muscle cells to insulin remains elevated until glycogen levels have been replenished.…”

Section: Figmentioning

confidence: 99%

Specific Desensitization of Glycogen Synthase Activation by Insulin in 3T3-L1 Adipocytes

Jensen¹,

Crosson²,

Kartha³

et al. 2000

Journal of Biological Chemistry

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A protocol was developed in 3T3-L1 adipocytes that resulted in the specific desensitization of glycogen synthase activation by insulin. Cells were pretreated for 15 min with 100 nM insulin, and then recovered for 1.5 h in the absence of hormone. Subsequent basal and insulininduced phosphorylation of the insulin receptor, IRS-1, MAPK, Akt kinase, and GSK-3 were similar in control and pretreated cells. Additionally, enhanced glucose transport and incorporation into lipid in response to insulin were unaffected. However, pretreatment reduced insulin-stimulated glycogen synthesis by over 50%, due to a nearly complete inhibition of glycogen synthase activation. Removal of extracellular glucose during the recovery period blocked the increase in glycogen levels, and restored insulin-induced glycogen synthase activation. Furthermore, incubation of pretreated 3T3-L1 adipocytes with glycogenolytic agents reversed the desensitization event. Separation of cellular lysates on sucrose gradients revealed that glycogen synthase was primarily located in the dense pellet fraction, with lesser amounts in the lighter fractions. Insulin induced glycogen synthase translocation from the lighter to the denser glycogen-containing fractions. Interestingly, insulin preferentially activated translocated enzyme while having little effect on the majority of glycogen synthase activity in the pellet fraction. In insulin-pretreated cells, glycogen synthase did not return to the lighter fractions during recovery, and thus did not move in response to the second insulin exposure. These results suggest that, in 3T3-L1 adipocytes, the translocation of glycogen synthase may be an important step in the regulation of glycogen synthesis by insulin. Furthermore, intracellular glycogen levels can regulate glycogen synthase activation, potentially through modulation of enzymatic localization.

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“…Changes in the phosphorylation state of glycogen synthase can be estimated indirectly by measuring its fractional velocity, which is defined as the ratio of the enzyme activity in the presence of low and high levels of its activator, glucose 6-phosphate (Bräu et al, 1997). Since the phosphorylation of glycogen synthase results in its inactivation when measured in the presence of low levels of glucose 6-phosphate, it follows that the higher the phosphorylation state of this enzyme, the lower its fractional velocity.…”

Section: Fractional Velocity Of Glycogen Synthasementioning

confidence: 99%

“…The homogenates were centrifuged at 2000·g for 10·min, and the supernatants further diluted fivefold with glycerol-free buffer before assay. The fractional velocity was determined using an assay that consists of measuring the activity of the enzyme at a sub-saturating near-physiological level of UDP-glucose (0.03·mmol·l -1 ) in the presence of either low (0.1·mmol·l -1 ) or high (5.0·mmol·l -1 ) glucose 6-phosphate concentrations (Bräu et al, 1997;James et al, 1998;Ferreira et al, 2001). Under these conditions, the reaction rates of glycogen synthase in the presence of low or high glucose 6-phosphate levels were linear with respect to both the amount of extract used and incubation time.…”

Section: Fractional Velocity Of Glycogen Synthasementioning

confidence: 99%

Lactate availability is not the major factor limiting muscle glycogen repletion during recovery from an intense sprint in previously active fasted rats

Raja

Mills

Palmer

et al. 2004

Journal of Experimental Biology

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SUMMARY It is not clear whether the amount of accumulated lactate is the main factor limiting muscle glycogen accumulation during recovery from an intense sprint performed by previously active fasted laboratory rats. To address this question, groups of fasted rats swam at moderate intensity for 30 min, each animal with a lead weight equivalent to 0.5% body mass attached to its tail,followed by a 3 min high intensity swim with a 10% lead weight and a recovery period of up to 2 hours afterwards. Moderately intense exercise for 30 min caused a decrease in muscle glycogen levels in the mixed, white and red gastrocnemius and the mixed quadriceps muscles, and a further rapid fall occurred in response to the 3 min sprint effort. During recovery, glycogen increased to comparable or above pre-sprint levels across all muscles, and this occurred to a large extent at the expense of net carbon sources other than lactate, with these carbon sources accounting for at least 36–65%of the glycogen deposited. The sustained dephosphorylation-mediated activation of glycogen synthase, but not the changes in glucose 6-phosphate levels, most probably played an important role in enabling the replenishment of muscle glycogen stores. In conclusion, our findings suggest that the amount of glycogen deposited during recovery from high intensity exercise in fasted animals is not limited by the amount of accumulated lactate.

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Regulation of glycogen synthase and phosphorylase during recovery from high-intensity exercise in the rat

Cited by 41 publications

References 57 publications

Overexpression of Protein Targeting to Glycogen in Cultured Human Muscle Cells Stimulates Glycogen Synthesis Independent of Glycogen and Glucose 6-Phosphate Levels

Overexpression of Protein Targeting to Glycogen in Cultured Human Muscle Cells Stimulates Glycogen Synthesis Independent of Glycogen and Glucose 6-Phosphate Levels

Specific Desensitization of Glycogen Synthase Activation by Insulin in 3T3-L1 Adipocytes

Lactate availability is not the major factor limiting muscle glycogen repletion during recovery from an intense sprint in previously active fasted rats

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