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Nutrition & Metabolism BioMed Central

Review Open Access
Metabolic aspects of low carbohydrate diets and exercise
Sandra J Peters* and Paul J LeBlanc

Address: Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada L2S 3A1
Email: Sandra J Peters* - sandra.peters@brocku.ca; Paul J LeBlanc - pleblanc@brocku.ca
* Corresponding author

Published: 30 September 2004 Received: 22 September 2004
Accepted: 30 September 2004
Nutrition & Metabolism 2004, 1:7 doi:10.1186/1743-7075-1-7
This article is available from: http://www.nutritionandmetabolism.com/content/1/1/7
© 2004 Peters and LeBlanc; licensee BioMed Central Ltd.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Following a low carbohydrate diet, there is a shift towards more fat and less carbohydrate
oxidation to provide energy to skeletal muscle, both at rest and during exercise. This review
summarizes recent work on human skeletal muscle carbohydrate and fat metabolic adaptations to
a low carbohydrate diet, focusing mainly on pyruvate dehydrogenase and pyruvate dehydrogenase
kinase, and how these changes relate to the capacity for carbohydrate oxidation during exercise.

Review mal oxygen uptake, 50–60 ml·kg-1·min-1) exercising at
Exercise, an acute bout of muscular activity, requires an a workload of 65–75% VO2max for 30–48 min.
expenditure of energy above resting levels. This required
mechanical energy is provided through the conversion of The sources of chemical energy that fuel exercising skeletal
metabolic fuels into ATP, the base currency of chemical muscle are available through endogenous depots (intra-
energy. Once produced, ATP is the only direct form of muscular glycogen and triglycerides) or exogenous
energy that is transferred and utilized by the contractile sources (plasma glucose and free fatty acids). In turn,
apparatus within the muscle. Fats are the predominant these exogenous and endogenous fuel sources are replen-
fuel source of resting skeletal muscle and during exercise, ished through dietary intake. As a result, there is an impor-
there is a complex interaction between skeletal muscle tant relationship between diet and fuel metabolism in
fat and carbohydrate (CHO) metabolism (see [1] for skeletal muscle.
review). When evaluating the effects of exercise on skel-
etal muscle fuel utilization, there are many facets that Diets low in carbohydrate content have become increas-
must be taken into consideration. These include inten- ingly popular as a method of weight loss. These diets that
sity and duration of the bout of exercise and the training limit daily dietary carbohydrate intake are termed low-car-
status of the subjects. During low intensity physical bohydrate diets (LCD). When evaluating the effects of
activity (25% maximal oxygen uptake (VO2max)), fat sup- LCD, there are a couple of factors that must be considered,
plies the majority of metabolic fuel to exercising skeletal as they may influence the measured outcome. These
muscle [2]. As physical activity increases to moderate lev- include the composition of the diet (since a LCD may
els (65–70% VO2max), there is a shift to more reliance on replace the missing CHOs with either protein or fat), and
CHO, specifically muscle glycogen [2]. However, at this the duration of the dietary period. For the purpose of this
level of physical activity, fat oxidation becomes increas- review, LCD will refer primarily to high-fat low-carbohy-
ingly important as the duration of exercise increases [2] drate isocaloric diets with <50 g of CHO per day, with a
or as training status improves [3]. The studies presented composition of 3–8% CHO, 22–46% protein, and 51–
in this review utilize moderately active subjects (maxi- 75% fat, and consumed for 3–6 days.

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and their blood glucose con- sites [7]. the relative activities of the PDK isoform centrations were maintained at ~5 mM throughout the population will determine the response of the PDH com. The emphasis of the present paper is on release from the sarcoplasmic reticulum is the primary adaptive skeletal muscle CHO and fat metabolism in stimulus that coarsely activates PDH whereas changes to humans. derived from carbohydrate sources. study. mammals are cited where necessary. activation or inactivation of PDH. Phosphatase activity is low at rest. 1:7 http://www. energy charge. exercise duration. which dephos. and exhaustion coincided with hypoglycemia catalyzed by a family of four PDK isoforms (PDK1-4) (~2. PDHa Page 2 of 8 (page number not for citation purposes) . tors to the acute regulation of PDH activation in the first carbohydrate diet few seconds or minutes. Data from other [10]. and PDH kinase (PDK). indicating that that skeletal tion by pyruvate or activation by energy charge (ATP/ADP muscle and liver glycogen stores were limiting under these ratio). a 6 d LCD was compared to a high-carbohydrate which phosphorylates and inhibits PDH [5]. catalyzed on activation of skeletal muscle PDHa activity during by an intrinsic PDH phosphatase (PDP). which maintain a cising skeletal muscle are still debatable. or PDP. the presence of increasing concentrations of Ca2+ ions (as cle metabolism during exercise and the importance of die. redox. The E1 sub. tions occur over hours or days and are independent of 1) Because it is highly regulated. and acetyl-CoA-to-free CoA the mechanism(s) responsible for these changes in exer. ratio and low pyruvate concentration. In addition. several metabolic and hormonal adaptations that improve fat oxidation and promote glycogen sparing in At rest. the regulation of the mitochondrial enzyme pyru. with towards fat or towards carbohydrate oxidation. redox (NADH/NAD+ ratio). These chronic altera- derived pyruvate to acetyl-coenzyme A (acetyl-CoA. Skeletal muscle glycogen content plex in acute situations. An intrinsic pair of phosphatases decreased during exercise but was still ~250 mmol gluco- (PDP1 and 2) catalyze the dephosphorylation and activa. Thus.Nutrition & Metabolism 2004. syl units/kg dry muscle at the end of exercise. PDH is mainly phosphorylated and inactive due to exercising skeletal muscle (see [4] for review). Phosphorylation of the complex is the LCD. At the onset tion of PDH [8]. exercise was terminated at the fer in their specificity for the different phosphorylation same time as the LCD trial. Subjects the first site being necessary for inactivation of the com.com/content/1/1/7 The present paper will briefly review human skeletal mus. in order to composition and re-feeding of carbohydrates following match PDH activation to the demand for CHO oxidation these altered diets affect these enzymes. long-term or chronic alterations Role of pyruvate dehydrogenase to the activation state of PDH can be accomplished In order to understand the regulation of carbohydrate oxi. During exercise. subjects exercised at Each of the covalent regulatory enzymes of PDH is subject 75% VO2max. to low intramuscular Ca2+ levels. would be expected during exercise).nutritionandmetabolism. either unit of PDH has three known phosphorylation sites. completed muscle glycogen depleting exercise and then plex. diet. In addition to the importance of intramitochondrial effec- Regulation of carbohydrate oxidation by low. high-carbohydrate diet. sion of either covalent modifier would alter the rate of versible oxidative decarboxylation of glycolytically. Effects of low-carbohydrate diet mining the rate of fat oxidation. At the end of the dietary intervention. Following the CoA ratio (see [7] for review). PDP1 is the isoform which is activated in of exercise during the high-carbohydrate trial. Fig. The subjects exhausted in ~47 min following to allosteric regulation. In this phorylates and activates PDH. moderately intense exercise (75% VO2max) [11]. the kinases dif. However. glucosyl units/kg dry muscle). activity ratio of PDK and PDP. high energy charge. due result of up-regulated fat and/or down-regulated carbohy. and acetyl-CoA-to-free conditions and at this intensity of exercise. and possibly redox effects of altered diets on key enzymes and how fatty acid fine-tune this activation (see [9] for review). and changes in the expres- PDH is a multi-enzyme complex which catalyzes the irre.4 mM) and low levels of muscle glycogen (~32 mmol which differ in their responsiveness to allosteric inhibi. through stable changes in the absolute levels of PDK and/ dation. and will compare recent studies that examine the pyruvate concentration. Ca2+ drate metabolism. The rate of activation of PDH is dependent on the vate dehydrogenase (PDH) must be carefully considered. and the other two sites acting as barrier sites to consumed either a LCD (< 3% energy from carbohydrate) hinder phosphatase activation [6]. shifting reliance from the two extremes. or a high-carbohydrate diet (86% carbohydrate) for 6 d. The amount of PDH in its In 1993. Putman and co-workers undertook a study to active form (PDHa) determines its activity and regulation examine the effects of a short term low-carbohydrate diet is achieved through reversible phosphorylation. while PDP2 is acti- tary CHO for metabolic energy production. it plays a pivotal role in acute changes in intramitochondrial effector determining the proportion of acetyl-CoA which is concentrations. It has been vated when insulin levels are increased during dietary well documented that diets low in carbohydrates result in manipulations [8]. thereby regulating flux through carbohydrate oxidation and indirectly deter. but could be the high PDK activity.

Following as little as 56 h on the LCD. Mg2+.nutritionandmetabolism. reflecting the increased energy demand for carbo. The first 15 minutes of exercise. Acetyl-CoA NADH. H+ PDK1 PDK2 PDP1 PDK3 PDP2 PDK4 . effectively impairing the capacity for carbohydrate sion. The increase in PDK activity during the were unable to adequately explain the difference in PDHa LCD was associated with impaired glucose clearance from activity between the trials based on acute changes in the the blood in response to an oral glucose load in health concentrations of intra-mitochondrial effectors. NAD. The authors sion with LCD. Ca2+. the 90 min area under the blood glucose and plasma insu- ing a role. ing that chronic regulation of the complex could be play. H+ Pyruvate. 3). Insulin. Page 3 of 8 (page number not for citation purposes) .Nutrition & Metabolism 2004. muscle following 6 days of a LCD [12] (Fig. activity increased maximally in the first 15 minutes of PDK activity was adaptively increased in human skeletal exercise. young men [14].Inhibitors + Activators NADH. respectively. CoA. 2). ADP Acetyl-CoA. oxidation and possibly promoting fat oxidation for the These studies suggest a selective increase in PDK4 expres- duration of exercise at this workload (Fig.Inhibitors ATP ADP. suggest.25-fold. PDHa activity was maximally activated in the in a linear fashion throughout the 6 d diet [13]. during an oral glucose tolerance Subsequent studies demonstrated adaptive alterations at test [14]. ATP PDHb Site 3 Site 1 Inactivating site P P P Site 2 Barrier sites Figure Activation 1 of pyruvate dehydrogenase enzyme complex control by a phosphorylation and dephosphorylation cycle Activation of pyruvate dehydrogenase enzyme complex control by a phosphorylation and dephosphorylation cycle. following ity increased in as little as 24 hr and continued to increase the LCD. 1:7 http://www. However. .com/content/1/1/7 CoA + NAD CO2 + NADH Pyruvate Acetyl-CoA PDHa + Activators Ca2+. the level of PDK with resultant changes in PDH activation. but the activation did not increased PDK activity in human skeletal muscle was asso- achieve the same levels as during the high-carbohydrate ciated with increased PDK4 mRNA and protein expres- trial. CoA. PDK activ- hydrate oxidation at this workload. lin concentration vs. time curves increased 2-fold and 1. NAD. which was maximally increased after 24 h [13].

for two reasons: 1) increased multi-site phosphorylation Page 4 of 8 (page number not for citation purposes) . the demand for muscle and liver glycogenolysis and mus- cle carbohydrate oxidation increases.1 exercise in both trials. 0. and a LCD (~3% carbohy- drate) was compared to a mixed diet (~55–60% carbohy- 0.4 cise at a slightly lower workload (65% VO2max). a Significantly different from day 0.6 ab exercise throughout the study.13]. Increased PDK activity would be expected to enhance multi-site phos- 3 * phorylation of the E1 subunit and make the complex PDHa (mmol min-1 kg ww-1) 2. would be expected to render the complex resistant to acti. so the initial levels of skeletal muscle glycogen and glycogen utilization was considerably lower following the LCD [11]. * denotes signifi- cance from LCD. Under normal dietary conditions the 2 predominant isoform in human skeletal muscle is PDK2. Thus. In a sub- sequent study. As exercise intensity increases. olytic flux to pyruvate was maintained [20]. Adapted from Peters et al. [12.2 y = 0. as the population of PDK4 isoform increased. skeletal muscle glycogen utilization and R2 = 0. PDK2 has a greater sensitivity to 0 inactivation by pyruvate than PDK4 [18]. 1:7 http://www.0659x + 0. which has a greater affinity for phosphorylation of site 1 1.5 (the inactivating site) of the E1 subunit [15-17].5 more resistant to dephosphorylation and activation by the phosphatase [6]. Although the initial skeletal muscle glycogen concen- tration was still ~50% lower in the LCD compared to the 0. As well. [11] and PDH activation are decreased following a LCD. in spite of the fact that PDK activity and PDK4 isoform would be expected to increase to a similar extent Figure Pyruvate of a LCD3dehydrogenase kinase (PDK) activity during six days as previous studies [13]. Adapted from Putman et al.nutritionandmetabolism. subjects were asked to refrain from intense 0. The object PDK activity (min-1) ab of the study was to match as closely as possible the ab 0.3 glycogen utilization during exercise between the two tri- a als.1002 mixed diet. However. Unlike the attenuated activation of PDHa at the onset of exercise which was observed in the 0 Putman study [11].5 LCD HCD * the complex to regulation by pyruvate. these effects were overridden Pyruvate dehydrogenase kinase (PDK) activity during six days when initial muscle glycogen levels were higher and glyc- of a LCD.9964 pyruvate accumulation were similar during the 30 min of 0. and therefore during intense exercise glycogenolytic flux vation during exercise.5 since this isoform has a greater affinity for both site 1 and site 2 [15-17]. b Significantly dif. there would 1 * be enhanced phosphorylation of the 2nd (barrier) site. It is clear from ferent from day 1. [11]. These stores are not These increased levels of PDK4 protein and PDK activity fully replenished following a very low carbohydrate diet. as observed by Putman et al.5 drate) instead of a high-carbohydrate diet [20]. the increased levels of PDK4 protein would render the com- Figureand Skeletal (PDHa) (LCD) 2at muscle rest highand pyruvate carbohydrate duringdehydrogenase exercise (HCD) in diets lowincarbohydrate its active form plex more resistant to activation due to increased PDK4 Skeletal muscle pyruvate dehydrogenase in its active form kinase activity even in the face of elevated muscle pyruvate (PDHa) at rest and during exercise in low carbohydrate concentrations [19].Nutrition & Metabolism 2004. (LCD) and high carbohydrate (HCD) diets. and/or 2) decreased sensitivity of 3. A confounding factor in the Putman study was that sub- jects had undergone intense glycogen depleting exercise protocols prior to both dietary interventions.com/content/1/1/7 of the PDH complex. Thus at the -10 0 10 20 30 40 50 Time (min) onset of exercise with increased glycolytic flux. these studies that the intensity and duration of the exer- cise play a role in the regulatory changes observed during exercise following a LCD. Subjects followed each 6 d dietary intervention with 30 min exer- 0. these authors observed that the activa- 0 2 4 6 8 tion during exercise was identical between the two condi- Time (days) tions.

In muscle biopsies LCD diet could be completely reversed in as little as 24 h taken 1 h after the re-feeding meal. PDHa activity was not affected by meal. and very little work has been done in human skeletal Significantly different from pre diet. Based on rodent studies of PDK activity.05 yet to be examined. since it would be expected that the high- tent of the diets was more important in determining the carbohydrate meal would suppress PDK4 gene expres- conversion of the complex in the basal state [22]. and there is increasing interest in the re-feeding. there is little information on how rapidly the LCD-adapted increase in PDK activity and PDK4 protein Figure Pyruvate after three 4dehydrogenase days of a LCDkinase with and (PDK)without activity n3before fatty acids and may be reversed with carbohydrate re-feeding.35 [23] fed rats one of three experimental diets to study the LCD effects on muscle metabolism: a LCD diet rich in safflower 0. ity was completely abolished with the addition of fish oil Subjects fasted for 20 h and then were given either a high- [22]. However.Nutrition & Metabolism 2004.nutritionandmetabolism. Jucker et al. How. increased transcription rate and mRNA concentration of Surprisingly. it has muscle decreased ~50–60% in approximately 4 h of re- been demonstrated that substituting only ~12% of the fat feeding [27]. it would 0. Adapted from Turvey et al. These data suggested that the skeletal muscle PDK 4 ever. a LCD rich in fish oil. the increase in PDK activity following a 28 d carbohydrate meal or a high-fat meal.26]. b Significantly different muscle. course reversion of PDK activity and PDK isoform expres- which are high in omega-3 unsaturated fatty acids. oxidation and glucose disposal in response to a challenge the study gave little information regarding how quickly Page 5 of 8 (page number not for citation purposes) . However.25 resistant compared to control or the fish oil-fed rats. this increasing resistance to LCDs decrease the activation of PDH in skeletal muscle at PDH complex activation was accompanied by increased rest and during exercise. these data the inclusion of fish oils suggesting that the total fat con. without measurement of PDK or PDH activity. The PDK activity (min-1) increased whole body glucose disposal in the fish oil-fed ab rats correlated with increased insulin-stimulated muscle 0. 75% fat) with fish oils. Thus.com/content/1/1/7 such as an insulinemic/euglycemic clamp. human skeletal muscle following fasting and re-feeding. or a high-carbohydrate (control) diet. early studies in cardiac muscle indi- from post LCD diet. with the key difference being that examined changes in PDK4 mRNA concentrations in the diet-induced increase in rat skeletal muscle PDK activ. 1:7 http://www. cated that re-feeding following 6 h starvation recovered PDHa activity to ~75% of normal levels in as little as 1–2 h. 4). 0. [28] recently earlier work in rodents. uated the diet-induced increase in PDK activity in human skeletal muscle [21] (Fig.00 Effect of re-feeding of carbohydrate following low-carbohydrate diet Pre Post In humans. PDK activity and PDK4 protein in skeletal composition of the fatty acids consumed. the time course of the response to re-feeding was longer. these authors found when fish oils were introduced into the high-fat diet [22]. sion. as the duration of the starvation period increased. atten. sion following a LCD in human skeletal muscle.30 LCD-n3 a oil. were unexpected. 0. PDHa Effect of fatty acid composition of low-carbohydrate diet activity recovered to only ~25% of control values after 4 h The studies presented in this review demonstrate that [24]. which is rich in fish oils enhances muscle carbohydrate However. In rodents. in such that after 48 h of starvation. Following 48 h starvation and are created equally. Pilegaard et al.15 appear that the deleterious effects of high-fat feeding on carbohydrate oxidation and glucose disposal may be 0. [21]. The effect of altered fat composi- tion on skeletal muscle metabolism during exercise has 0.10 ameliorated when the dietary composition of fatty acids are considered carefully. not all LCDs fast or high-fat diet [25. However. there is evidence from animal studies that a LCD gene was very sensitive to metabolic disturbances. Most re- Pyruvate dehydrogenase kinase (PDK) activity before and feeding studies have used prolonged fasting as a perturba- after three days of a LCD with and without n3 fatty acids. In fact. in both rat and human skeletal muscle in the the PDK4 isoform regardless of the composition of the resting and basal state. Recently. These results are similar to In human skeletal muscle.20 disposal of glucose through oxidation as determined with stable isotope tracer technology [23]. In later rodent studies. mediated through increased PDK PDK activity. which correlated with the duration of the activity and isoform expression. a tion. little is known about the time in a LCD (~3% carbohydrate. They found that the safflower-fed rats were insulin 0.

even though there acid uptake. fatty acid oxidation were higher during exercise following PDHa activation is attenuated during intense exercise and a fat-rich LCD (21% CHO) when exercise training was this is due at least in part to increased PDK activity and combined with the diet perturbation [32]. This is further supported by the fact that in well trained human subjects.3 to 2. activity increased almost 2-fold. there is evidence in human skeletal muscle for increased Although a 6 d LCD (3% CHO) did not alter β-HAD activ- activities of several regulatory enzymes and proteins in ity [12]. maximal CPT activity was mod- Regulation of fat oxidation by low-carbohydrate diet estly increased following a prolonged (4 week) very low There is little information regarding the skeletal muscle LCD (<20 g CHO). Taken together. expression and protein content were unaffected by the diet [31]. Key steps include delivery of fatty untrained subjects. Similarly. In terms of muscle fatty determined by electron microscopy). Helge et al. increasing fatty acid avail. PDK4 gene expression. With re-feeding of carbohy- fold at 10 weeks. mitochondrial uptake and more carbohydrate restricted diet (3% CHO) for 6 d did oxidation through carnitine palmitoyl transferase I (CPT not alter CS activity in human skeletal muscle [12]. Impaired glucose clearance in response to an oral glucose and mRNA levels following a 5 d LCD (19% CHO) [31]. expression or mRNA concentrations of the pertinent enzymes involved in fat oxidation. depending on the fatty acid composition drates. but this may be dependent on the fatty I enzyme activity capacity was increased up to 1. skeletal muscle LPL could potentially suggest an increase in oxidative capacity. acid composition of the diet. 1:7 http://www. with the largest increases demonstrated in type IIb fibers [40]. skeletal muscle CPT I is unaffected by exercise. muscle during prolonged LCD perturbations as well. tion. In I). a FABPpm respectively). Thus. and very few have Increased activity of a key marker enzyme for fatty acid measured the more physiologically relevant concentra. while FABPpm gene CHO) [41]. PDK activity drops to pre-diet levels in 3 h. [36] observed increased β-HAD activ- skeletal muscle fatty acid uptake and oxidation following ity following a 4 week LCD (20% CHO) perturbation in high fat diets or LCD. as well as plasma In summary. recent research has demonstrated that there was no differ- ability to the muscle and increasing intramuscular triglyc. A recent study examining was only documented in the soleus muscle. results from some rat studies have demonstrated acyl CoA dehydrogenase (β-HAD)).Nutrition & Metabolism 2004. 39]. muscle uptake of fatty acids and very Conclusions low density lipoprotein triglycerides. the adaptive change in PDK activity be prolonged enough to evoke a significant change in observed in human skeletal muscle is rapidly reversed activity or gene expression of this enzyme which regulates with re-feeding of carbohydrates. they found no increase in acids to the muscle through muscle lipoprotein lipase either whole body VO2max or CS activity. tolerance test was observed in healthy subjects following However. Still. However. in skeletal muscle of rats fed a high-fat diet. PDK activity increases in as little as 24 h on a LCD. In human skeletal whether this measurements included CPT I and CPT II muscle.25-fold) after only mental exercise following a 5 week high fat LCD (25–30% 5 d on a moderate LCD (20% CHO). most studies restrict their measurements to gene activity together [35]. If intense exercise is restricted and muscle Page 6 of 8 (page number not for citation purposes) . enzyme activity following a 6 d LCD (~3% CHO) [12]. This was demonstrated at the level of maximal LCD. these studies sug- fully recovered in as little as 3 h in resting human skeletal gest that the short term 5–6 d LCD perturbation may not muscle [29]. and general oxidative modest increases in CS activity of approximately 20% [37- capacity (marker enzyme citrate synthase (CS)). since a significant increase with carbohydrate re-feeding. ence in human skeletal muscle mitochondrial density (as eride content significantly [30].com/content/1/1/7 the fasting-induced increase in PDK activity was reversed I slow oxidative muscle fibers. Although the increase in β-HAD activity in In response to a 4 week adaptation to a high fat (~62% human skeletal muscle and possibly CS in rat muscle fat) moderate LCD (~20% CHO). suggesting that (LPL). beta-oxidation has been observed in human skeletal tions of enzyme activity or protein concentration. and not the carbohydrate re-feeding following a 6 d LCD indicates extensor digitorum longus following 8 weeks of a high-fat that PDK activity is rapidly reversed and PDHa activity has LCD (0% CHO) [34]. following a 6 d LCD in human subjects. of the diet [33]. In general.nutritionandmetabolism. This decreased activation of PDHa decreases carbohydrate and increases fat oxidation during In human studies. fatty acid beta-oxidation (marker enzyme β-hydroxy contrast. sarcolemmal fatty acid transporters and plasma the increase in beta-oxidation was specific rather than a membrane fatty acid binding proteins (FAT/CD26 and generalized increase in oxidative capacity. increased gene although this does not appear to correlate with mRNA expression of CPT I mRNA appears to be restricted to type concentration. although it is not clear from this data adaptation on "the fat side" to a LCD. and PDK activity increases linearly over the 6 d. In another rat study. regardless of potential transport of fatty acids into the mitochondria for oxida- changes in PDK4 mRNA expression [28]. CPT only 56 h of LCD. there is evidence that the FAT/CD36 protein was an increase in fat oxidation at rest and during incre- and mRNA were increased modestly (1.

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