The “glycogen shunt” in exercising muscle: A role for glycogen in muscle energetics and fatigue

Shulman, Robert G.; Rothman, Douglas L.

doi:10.1073/pnas.98.2.457

Cited by 143 publications

(113 citation statements)

References 29 publications

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“…The parallel activation of glycogen synthesis and degradation was first shown in exercised muscle and is referred to as the 'glycogen shunt'. 44 Although energetically unfavorable, the shunt has been justified by the capacity of glycogen to rapidly generate energy at a specific time point, with a faster ATP production per molecule from glycogen-derived glucose than from extracellular hexose. 45 In the brain, the shunt hypothesis has been proposed for astrocytic glycogen; 46 here we show that it also takes place in neurons and that its absence makes these cells more vulnerable to oxygen depletion.…”

Section: Discussionmentioning

confidence: 99%

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Sáez

Durán

Sinadinos

et al. 2014

J Cereb Blood Flow Metab

180

165

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Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that-against general belief-neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress.

show abstract

Section: Discussionmentioning

confidence: 99%

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Sáez

Durán

Sinadinos

et al. 2014

J Cereb Blood Flow Metab

180

165

View full text Add to dashboard Cite

show abstract

“…Rather, since the decline in muscle function occurred rather early during contraction (between 1 and 30 min), we can speculate that impaired steady-state aerobic efficiency (force declined modestly from 30 to 60 min) reflects an altered relative contribution to tension development from the various fiber types within the muscle group (24,25). This may have been precipitated by an early failure of glycolysis to support aerobic fiber function during the transition from rest, since it has been postulated that glycolytic flux per se is important for the modulation of mitochondrial redox state (26,27).…”

Section: Discussionmentioning

confidence: 99%

The Experimental Type 2 Diabetes Therapy Glycogen Phosphorylase Inhibition Can Impair Aerobic Muscle Function During Prolonged Contraction

et al. 2006

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Glycogen phosphorylase inhibition represents a promising strategy to suppress inappropriate hepatic glucose output, while muscle glycogen is a major source of fuel during contraction. Glycogen phosphorylase inhibitors (GPi) currently being investigated for the treatment of type 2 diabetes do not demonstrate hepatic versus muscle glycogen phosphorylase isoform selectivity and may therefore impair patient aerobic exercise capabilities. Skeletal muscle energy metabolism and function are not impaired by GPi during high-intensity contraction in rat skeletal muscle; however, it is unknown whether glycogen phosphorylase inhibitors would impair function during prolonged lowerintensity contraction. Utilizing a novel red cell-perfused rodent gastrocnemius-plantaris-soleus system, muscle was pretreated for 60 min with either 3 mol/l free drug GPi (n ‫؍‬ 8) or vehicle control (n ‫؍‬ 7). During 60 min of aerobic contraction, GPi treatment resulted in ϳ35% greater fatigue. Muscle glycogen phosphorylase a form (P < 0.01) and maximal activity (P < 0.01) were reduced in the GPi group, and postcontraction glycogen (121.8 ؎ 16.1 vs. 168.3 ؎ 8.5 mmol/kg dry muscle, P < 0.05) was greater. Furthermore, lower muscle lactate efflux and glucose uptake (P < 0.01), yet higher muscle VO 2 , support the conclusion that carbohydrate utilization was impaired during contraction. Our data provide new confirmation that muscle glycogen plays an essential role during submaximal contraction. Given the critical role of exercise prescription in the treatment of type 2 diabetes, it will be important to monitor endurance capacity during the clinical evaluation of nonselective GPi. Alternatively, greater effort should be devoted toward the discovery of hepatic-selective GPi, hepatic-specific drug delivery strategies, and/or alternative strategies for controlling excess hepatic glucose production in type 2 diabetes.

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“…Although there are substantial differences from yeast, in all cases, the glycogen shunt acts to maintain metabolic and ATP homeostasis during quasi-steadystate conditions in which there are periodic large increases in glycolysis (23)(24)(25). Results in cancer cells suggest that, under at least transient conditions of high glucose, the glycogen shunt may play a similar important role for maintaining homeostasis and provide a basis for explaining excess lactate production.…”

mentioning

confidence: 84%

“…We perform a mass balance calculation of the carbon, redox, and ATP flows in the glycogen shunt, glycolysis, and futile cycling to determine the fractional production of pyruvate, NADH, and glycogen/trehalose per glucose. Our previous application of this analysis to muscle and brain (23)(24)(25) was able to explain aerobic lactate production as a consequence of the relative fluxes of the glycogen shunt (both synthesis and degradation) and glycolysis.…”

Section: Significancementioning

confidence: 99%

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Homeostasis and the glycogen shunt explains aerobic ethanol production in yeast

Shulman

Rothman

2015

Proc. Natl. Acad. Sci. U.S.A.

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Aerobic glycolysis in yeast and cancer cells produces pyruvate beyond oxidative needs, a paradox noted by Warburg almost a century ago. To address this question, we reanalyzed extensive measurements from 13 C magnetic resonance spectroscopy of yeast glycolysis and the coupled pathways of futile cycling and glycogen and trehalose synthesis (which we refer to as the glycogen shunt). When yeast are given a large glucose load under aerobic conditions, the fluxes of these pathways adapt to maintain homeostasis of glycolytic intermediates and ATP. The glycogen shunt uses glycolytic ATP to store glycolytic intermediates as glycogen and trehalose, generating pyruvate and ethanol as byproducts. This conclusion is supported by studies of yeast with a partial block in the glycogen shunt due to the cif mutation, which found that when challenged with glucose, the yeast cells accumulate glycolytic intermediates and ATP, which ultimately leads to cell death. The control of the relative fluxes, which is critical to maintain homeostasis, is most likely exerted by the enzymes pyruvate kinase and fructose bisphosphatase. The kinetic properties of yeast PK and mammalian PKM2, the isoform found in cancer, are similar, suggesting that the same mechanism may exist in cancer cells, which, under these conditions, could explain their excess lactate generation. The general principle that homeostasis of metabolite and ATP concentrations is a critical requirement for metabolic function suggests that enzymes and pathways that perform this critical role could be effective drug targets in cancer and other diseases.Warburg effect | glycogen synthesis | Pasteur effect | glycolysis | homeostasis A challenge to contemporary biological research was sounded by Steve McKnight, who noted (1) that "the low lying fruit that could be picked by molecular biologists without considering the metabolic state of the cell, tissue or organism is largely gone." He proposed that now we must seek an understanding of the reciprocity between the regulatory state driven by signals from transcription factors and the dynamics of metabolic control. This was a timely call because the interactions of genetics and metabolism, developed in yeast research (2), was becoming paradigmatic in cancer studies (3-5). Because both cancer cells and yeast derive metabolites and energy from glucose, the relations of yeast metabolism with genetic expression, rather well understood in the glucose pathways, are providing an informative parallel for the study of cancer cells (6, 7).The traditional approach attributes cellular metabolism to the kinetic properties of the component enzymes, as summarized in the comprehensive biochemistry textbooks, and then correlates changes in enzyme activity with differences in cell phenotype (3, 4). In our opinion, this approach neglects the interconnected nature of biochemical pathways that can be measured noninvasively, using magnetic resonance spectroscopy (MRS) (8-13), and the ability to quantitatively understand the sharing of biochemical control betw...

show abstract

The “glycogen shunt” in exercising muscle: A role for glycogen in muscle energetics and fatigue

Cited by 143 publications

References 29 publications

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

The Experimental Type 2 Diabetes Therapy Glycogen Phosphorylase Inhibition Can Impair Aerobic Muscle Function During Prolonged Contraction

Homeostasis and the glycogen shunt explains aerobic ethanol production in yeast

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