Exercise Metabolism

PAUL A. MOLÉ , in Exercise Medicine, 1983

4 DIET AND GLYCOGEN RESTITUTION

Muscle glycogen does not vary significantly over the course of normal daily activity as long as usual meal patterns are followed (73). But with starvation, its concentration gradually falls over a 5- to 6-day period. On calorically adequate but virtually CHO-free diet, glycogen falls in muscle but more slowly than during starvation (73). Glucose or fructose infusion increases muscle glycogen content only modestly in a 6-hour period of rest (73). However, this is not the case in the recovery of muscle previously exercised and glycogen depleted. Even without food intake in the immediate recovery period, muscle glycogen is resynthesized, both in rest and during active recovery at a reduced exercise intensity, presumably using blood glucose from accelerated glyconeogenesis (4), and using enhanced lactate uptake by muscle (67). There remains, however, a controversy as to the extent lactate disappearance during recovery represents oxidation and glycogen resynthesis (17,18,49,67). Nevertheless, complete restitution of muscle glycogen requires food intake, since it has been shown that endogenous substrates do not lead to full recovery, at least over 4–5 (101) to 20 hours (73). A mixed diet does replenish glycogen by between 24 hours (101) to 46 hours (118). Presumably this difference in rate of restitution depends on the intensity and duration of the preceding exercise and the extent the exercise has depleted muscle glycogen. Also, some of the differences in the glycogen restitution rate of the last two studies, which used different exercise protocols, could be related to differences in blood glucose and insulin levels produced by each exercise. For the prolonged hard exercise of Piehl, blood glucose and insulin levels fell (2–4) and remained low for some time during recovery, whereas in the short intermittent severe exercise of MacDougall, blood glucose and insulin were elevated at the end and following exercise. So presumably, there is accelerated resynthesis of glycogen in the latter case thereby promoting significant glycogen accumulation within 2 hours even without food, and complete recovery occurs in 24 hours with consumption of a 3100-kcal mixed diet.

For muscle glycogen depletion produced by prolonged exercise, it appears the composition of food intake is important in determining both the rate and extent of glycogen repletion. With a calorically adequate diet of fat and protein, glycogen resynthesis is slow and incomplete even after 4 days (73). In contrast, a day of fasting after exhaustive exercise, followed by CHO ingestion, nearly restores glycogen in the next 24 hours and produces "supercompensation" of glycogen stores in 2 days (73). Supercompensation means the glycogen stores increase to a level markedly above the predepletion content. It can amount to three to four times control over a 3-day period of CHO feeding (16). This supercomposition of glycogen repletion produced by exhausting exercise and CHO feeding is specific to the muscles exercised; nonexercised muscles increase their glycogen content only slightly (16).

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Muscle physiology: responses to exercise and training

José-Luis L. Rivero , Richard J. Piercy , in Equine Exercise Physiology, 2008

Glycogen depletion

Muscle glycogen concentration declines rapidly during maximal exercise 154,162 to an extent that varies between 30% and 50% depending on the number and frequency of exercise bouts. 161 This degradation affects both proglycogen and macroglycogen. 164 Glycogen depletion occurs most rapidly in the glycolytic low oxidative IIX fibers simultaneously with lactate production. 5 Although glycogen depletion is not considered to be a major factor contributing to fatigue during anaerobic exercise, 76 its depletion is associated with diminished anaerobic power generation and hence the capacity for high-intensity exercise. 165,166

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Magnetic Resonance Spectroscopy of Muscle Bioenergetics

Kevin K. McCully , ... Britton Chance , in NMR in Physiology and Biomedicine, 1994

IX MRS MEASUREMENTS OF MUSCLE METABOLISM USING OTHER NUCLEI

Studies have measured muscle glycogen levels using natural abundance 13C and showed very good agreement with glycogen levels determined from muscle biopsies (Taylor et al., 1992). This study used unlocalized spectroscopy with a 4.7-T magnet to obtain glycogen measurements every 5 min. The reproducability of the measurements was excellent, with a coefficient of variation of 4%, compared to a coefficient of variation from the muscle biopsies of 9%. While 4.7-T magnets are relatively rare, this study shows promise for MRS measurements to noninvasively identify muscles in different states of glycogen depletion/repletion. Other studies have used 1H MRS to measure levels of deoxymyoglobin in muscle (Wang et al., 1992). This will be a useful measure of the ability to deliver oxygen to muscle (Jue, this volume). Still other studies have shown the feasibility of measuring lactate levels directly using 1H MRS (Hetherington et al., 1989). In this study lactate levels were measured every 2.7 min in the finger flexor muscles in one subject before and after exercise to exhaustion. At the end of exercise a large peak related to the C3 resonance of lactate was seen, consistent with a decrease in muscle pH from 7.1 to 6.0. Then during recovery from exercise the lactate signal decline at a rate of 6.3% per minute. Lactate measurements show great promise for the understanding of glycolytic muscle metabolism in vivo. The difficulty with the 1H measurements is that lactate and deoxymyoglobin levels are small compared to water and fat peaks, thus requiring complicated suppression techniques to eliminate these peaks.

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Therapeutic Exercise

Rochelle Coleen Tan Dy , in Braddom's Rehabilitation Care: A Clinical Handbook, 2018

Rapid Glycolysis (Lactic Acid System)

Glycolysis uses carbohydrates, primarily muscle glycogen, as a fuel source. In the absence of oxygen, the anaerobic pathway is utilized, producing lactic acid. Anaerobic glycolysis begins and dominates for approximately 1.5–2 minutes to provide fuel for high-energy burst activities such as middle-distance sprints (400-, 600-, and 800-m runs) or weightlifting. Lactic acid accumulation limits physical activity as it leads to fatigue and diminished performance. However, under aerobic conditions, lactate serves as a metabolic intermediate, which is converted into pyruvic acid and subsequently into energy (ATP), or it can be used to produce glucose (hepatic gluconeogenesis) via the Cori cycle.

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Foods and Nutrition for Exercise

GABE MIRKIN , in Exercise Medicine, 1983

2 DEPLETION

Marathon runners may develop symptoms of muscles glycogen depletion (the "wall") anywhere from the fifteenth to twenty-sixth mile of a marathon. To improve glycogen stores in muscle, it is necessary to exercise them almost to the point of glycogen depletion about once a week. Following a long run, for example, muscle will take up increased amounts of carbohydrate. Runners training for marathons use this depletion-restoration process to increase muscle glycogen stores prior to long runs. Marathon runners will run more than 15 miles once a week, bicycle racers will ride for 4–6 hours, and the cross-country skiers may spend 10–12 hours on a continuous skiing program.

Because of the increased popularity of marathons, many people are participating in these long (26.2 miles) races before they have achieved enough training to improve muscle glycogen stores. That is why at the finish of many marathons, there are large numbers of runners staggering, limping, and in pain. These people are consuming their own muscle as fuel at the end of the race.

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Carbohydrate Metabolism During Exercise

Kelly M. Hammond , ... James P. Morton , in Muscle and Exercise Physiology, 2019

11.5.7 Muscle Glycogen Threshold

Although it is now accepted that muscle glycogen availability is a potent regulator of the adaptive responses of skeletal muscle to exercise training, the level of absolute glycogen required to augment the pathways regulating mitochondrial biogenesis is currently unknown. However, it appears that a "glycogen threshold" may exist, whereby a critical absolute level of glycogen must be exceeded in order for significant activation of specific cell-signaling pathways to occur. The majority of studies that adopt a low glycogen model commence exercise with glycogen concentrations between 100–300   mmol·(kg   d.w.)−1, where the activity of key cell-signaling kinases, transcription factors, and transcriptional coactivators and expression of various metabolic genes are augmented when compared with exercise commenced with high (350–900   mmol·(kg   d.w.)−1) glycogen (see Fig. 11.7). As such, it would appear important that exercise is commenced with muscle glycogen concentrations below 350   mmol·(kg   d.w.)−1 when undertaking a train-low exercise session. Nonetheless, it also appears that significant activation of cell-signaling pathways controlling mitochondrial biogenesis can still be achieved with high preexercise glycogen concentrations as long as a critical absolute amount of glycogen is exceeded during exercise (and some exercise is therefore performed under conditions of low glycogen). For instance, Impey et al. (2015) demonstrated that exhaustive exercise induces significant activation of AMPK and expression of transcription factors (p53, Tfam) and coactivators (PGC-1α), even when commenced with high glycogen levels (600   mmol·(kg   d.w.)−1). This is likely due to the fact that subjects surpassed a critical level of glycogen (~350   mmol·(kg   d.w.)−1) during exercise and reached exhaustion at very low levels (~100   mmol·(kg   d.w.)−1), therefore performing a significant proportion of exercise with low muscle glycogen. Although significant activation of cell-signaling cascades appears possible with high preexercise glycogen levels, what is clear is that significantly more "work" is required to achieve the same signaling effects, whereby commencing exercise with low glycogen induces "work-efficient" cell signaling related to mitochondrial biogenesis. For instance, the aforementioned work demonstrates that training with low preexercise (~300   mmol·(kg   d.w.)−1) glycogen induces a significant activation of AMPK in significantly less time (~60   min) than when training is commenced with high glycogen.

Figure 11.7. Summary of studies demonstrating differential metabolic responses of skeletal muscle in response to exercise commenced in conditions of high or low muscle glycogen availability. Studies are categorized into those examining a) cell signalling, b) gene expression and c) muscle contractile capacity and post-exercise signalling Shaded area represents proposed muscle glycogen threshold. Red bars represent low CHO trials and green bars represent high CHO trials. The width of the bar represents starting and end point of muscle glycogen during the relevant exercise trials.

 Taken from Fig. 11.2, Impey, S.G., et al., 2018. Sports. Med, under the terms of the Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0/.

ACC, acetyl-CoA carboxylase; AMPK, 5ʹ adenosine monophosphate-activated protein kinase; Ca2+, calcium; COX, cytochrome c oxidase; p38, p38 mitogen-activated protein kinase; p70S6K, ribosomal protein S6 kinase beta-1; PDK4, pyruvate dehydrogenase lipoamide kinase 4; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Tfam, transcription factor A.

Further support for the notion of a glycogen threshold is also provided from studies that have fed CHO during exercise. Indeed, when glycogen utilization during exercise is attenuated through exogenous CHO supplementation (i.e., glycogen sparing) and hence does not surpass a "critical limit," AMPK activity is reduced (Akerstrom et al., 2006). Interestingly, CHO supplementation prevented muscle glycogen concentrations surpassing 300   mmol·(kg   d.w.)−1 (similar to that of the proposed "critical threshold"), whereas when glycogen was reduced to 200   mmol·(kg   d.w.)−1 in the placebo trial, a significant activation of AMPK occurred (Akerstrom et al., 2006). In contrast, when exogenous CHO supplementation does not spare muscle glycogen (and therefore allows depletion below a "critical limit") (< 200   mmol·(kg   d.w.)−1) AMPK activity is not suppressed (Lee-Young et al., 2006). While training with glycogen concentrations below a critical limit appears beneficial for the activation of cell-signaling cascades regulating mitochondrial biogenesis, it appears that keeping glycogen at these levels may impair the regulation of postexercise muscle protein synthesis. Indeed, subsequent work from Impey et al. (2016) demonstrates that p70S6K activity is suppressed when glycogen concentrations reach very low levels (~100   mmol·(kg   d.w.)−1) despite feeding leucine enriched whey protein. However, repletion of muscle glycogen to ~250   mmol·(kg   d.w.)−1, via sufficient postexercise CHO provision, appears to re-activate p70S6K activity.

In addition to regulating cell-signaling pathways controlling mitochondrial biogenesis and muscle protein synthesis, muscle glycogen also appears to regulate SR calcium handling and thus skeletal muscle function, whereby contractile properties are impaired when glycogen concentrations fall below a critical limit. Chin and Allen (1997) elegantly demonstrated that when recovery from glycogen reducing contractions occurs in the absence of glucose and thus glycogen remains low, fiber bundles fatigue at a faster rate and show reduced tetanic Ca2+ transients in a subsequent fatigue test. These findings have been subsequently confirmed in human skeletal muscle, where an impairment in SR Ca2+ release rate and subsequent power output are apparent under conditions of low muscle glycogen (Duhamel, Perco and Green, 2006; Ortenblad et al., 2011; Gejl et al., 2014). Intriguingly, this impairment appears to occur at muscle glycogen concentrations below 300   mmol·(kg   d.w.)−1, similar to the proposed critical threshold required to significantly activate cell-signaling pathways regulating mitochondrial biogenesis. Given the importance of Ca2+ for EC coupling and subsequent muscle contraction, it appears that low glycogen concentrations may inhibit the ability of skeletal muscle to contract and muscle fibers may fatigue more rapidly. When taken together, these data further allude to a potential muscle glycogen threshold, surmising that low muscle glycogen may not only enhance the activation of pathways regulating mitochondrial biogenesis, but also regulate skeletal muscle contractile properties and postexercise muscle protein synthesis if kept at critically low levels.

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The Influence of Gender Differences in Metabolism upon Nutritional Recommendations for Athletes

MARK A. TARNOPOLSKY MD, PhD , in Principles of Gender-Specific Medicine, 2004

VI. Carbohydrate Loading and Carbohydrate Dietary Manipulations for Endurance Activities

It has been known for decades that muscle glycogen stores are positively correlated with endurance exercise performance at intensities from 60–75% of maximal aerobic power [66,67]. Furthermore, dietary manipulations that lead to a higher carbohydrate intake can enhance endurance exercise performance at aforementioned intensities [68,69]. The dietary manipulation whereby an athlete increases carbohydrate intake and tapers their exercise training is termed carbohydrate loading and results in an increase in muscle glycogen store improvement and endurance exercise performance improvement [68,69].

The original studies that examined carbohydrate loading used exclusively or predominantly male subjects [68–71]. Based upon the aforementioned gender differences in carbohydrate metabolism, our group hypothesized that there may be gender differences in the ability to carbohydrate load [13]. Well-trained male and female athletes were given two dietary regimens providing 75% (LOAD) and 55% (HABITUAL) of total energy intake. They consumed each diet for 4 days before completing cycle ergometry for 60 min @ 75% VO2peak followed by a performance ride to exhaustion at 85% VO2peak. The males increased resting muscle glycogen content by 45%, which was correlated with a similar increase in performance, whereas the females showed neither an increase in glycogen content nor in exercise performance [13]. Subsequent work from Spreit et al supported these findings by showing that well-trained female athletes showed only minimal increases in muscle glycogen and exercise performance following carbohydrate loading and concluded that, "… the magnitude [of glycogen loading] was smaller than previously observed in men." [72].

Given that there do not appear to be any significant gender differences in hexokinase or GLUT-4 (see previous), we had hypothesized that one of the major factors responsible for the gender difference in the ability to carbohydrate load was the lower relative and absolute energy intake by the females which meant that females consumed less carbohydrate on a per kilogram body weight basis (<7 g/kg/day). In studies evaluating carbohydrate loading in men, the corresponding amount of dietary carbohydrate amounts to >8g/kg/day [13,69,71]. Hence, if men and women are given dietary carbohydrate as a proportion of total energy intake, females are less likely to exceed a carbohydrate intake of 8 g/kg/day. Therefore, we completed a study where male and female athletes consumed three diets (habitual energy intake [55% CHO]; high carbohydrate intake [75% CHO]; and high carbohydrate + extra energy [75% CHO + 30% more energy than habitual intake] and muscle glycogen was measured) [32]. We found that increase in the percentage carbohydrate intake was insufficient for the females to increase muscle glycogen stores, yet when the additional energy was provided (hence greater CHO/kg body mass), there was a significant increase in muscle glycogen content [32]. These results were confirmed in a study where the ability to carbohydrate load in response to very high amounts of dietary carbohydrate (>12 g/kg fat-free mass/day) was evaluated in men and women (in both follicular and luteal phases of the menstrual cycle) [47]. This study found similar increases in muscle glycogen for both men and women in response to the load and between the menstrual cycle phases [47].

We have also compared the glycogen resynthesis rate in males and females following endurance exercise (90 min @ 65% of VO2peak) with placebo, carbohydrate (1 g·kg−1 CHO) and carbohydrate/protein/fat (0.7g/kg−1 CHO/0.1 g/kg−1 PRO/0.02 g/kg−1·d−1 FAT) supplements given immediately and 1 hour after exercise. The rate of glycogen resynthesis in the first 4 hours was higher for the CHO and CHO/PRO/FAT as compared to placebo trials, yet was not significantly different between the genders [33]. These results confirmed that the glycogen resynthesis rates for men and women were similar in the postexercise period providing that the carbohydrate was expressed relative to body weight. Indirectly, these results provide some support for the aforementioned carbohydrate loading observations.

Many studies have found that the provision of exogenous carbohydrate during endurance exercise can delay the onset of fatigue and promote higher glucose oxidation rates in the latter stages of endurance exercise [73–77]. The majority of these studies had been completed with predominantly male subjects [73,76,77], and very few studies have examined the effect of exogenous carbohydrate intake on endurance exercise metabolism and performance in females [34,35]. One study found an 11–14% increase in exercise performance in young women during both the follicular and luteal phase of the menstrual cycle with a 6% glucose solution [35]. These findings have been extended by work showing greater improvement in performance from 6% glucose solution ingestion in both the follicular [19%] and luteal [26%] phase of the menstrual cycle [34]. We have extended these findings by showing that females oxidized a greater proportion of exogenous carbohydrate (8% carbohydrate solution) with a corresponding greater attenuation of endogenous glucose oxidation as compared with males during exercise [78].

In summary, it appears that the apparent inability for females to carbohydrate load was due to their low habitual energy intake which resulted in a relative carbohydrate intake of <8 g/kg/day. With additional energy and an increase in the proportion of carbohydrate, females can increase muscle glycogen content and performance. Similarly, in the immediate postexercise period, females and males show similar rates of glycogen resynthesis. Finally, males and females show similar responses to exogenous carbohydrate provision during exercise and both increase performance.

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Inborn Errors of Carbohydrate, Ammonia, Amino Acid, and Organic Acid Metabolism

J. Lawrence MerrittII, Renata C. Gallagher , in Avery's Diseases of the Newborn (Tenth Edition), 2018

Muscular Glycogen Storage Diseases

The most common and significant form of muscular GSD is type II, commonly called Pompe disease (acid alpha-glucosidase deficiency (abbreviated as GAA), also known as acid maltase deficiency or lysosomal α-1,4-glucosidase deficiency). This is the only GSD that is also a lysosomal storage disease (LSD), and it was the first identified LSD. Glycogen accumulates within the lysosome because of a defect in lysosomal-mediated degradation of glycogen. As for some other LSDs, enzyme replacement therapy has been developed for Pompe disease. This is the only current effective therapy for this disease.

Pompe disease has an estimated incidence of 1 in 40,000 in the Netherlands, based on the country's screening for three common mutations in newborn blood spots. The incidence ranges from 1 in 57,000 for late-onset disease to 1 in 138,000 for classic infantile disease (Ausems et al., 1999; Mechtler et al., 2012).

The classic infantile presentation of Pompe disease is hypotonia and hypertrophic cardiomyopathy. Creatine kinase, lactate dehydrogenase, and aspartate aminotransferase are elevated. The electrocardiogram is abnormal with a short PR interval and giant QRS complex in all leads, suggesting biventricular hypertrophy (Fig. 22.2). Late-onset presentations are of myopathy and have been diagnosed as early as the 2nd year of life. Diagnosis is made through the identification of decreased GAA activity in dried blood spots, fibroblasts, or muscle and confirmed via sequencing of the GAA gene (Zhang et al., 2006; Winchester et al., 2008). If the diagnosis is suspected, muscle biopsy can be avoided through blood spot and DNA testing but if performed will demonstrate vacuolar myopathy with glycogen storage within lysosomes and free glycogen in the cytoplasm demonstrated by electron microscopy. The vacuoles are periodic acid-Schiff positive, digestible by diastase, and positive for acid phosphatase.

Decisions regarding which disorders are included on a state's NBS panel are made by each state, and some states now include Pompe disease. NBS in other countries has led to the initiation of early enzyme replacement therapy, which demonstrates improvements in cardiac size, muscle pathology, growth, and gross motor function in affected individuals but not in arrhythmias such as Wolff–Parkinson–White or in dysphagia or osteopenia (Chien et al., 2009; van Gelder et al., 2015). Long-term follow-up of early-treated individuals has demonstrated increased life span and increased ambulation with individuals not requiring mechanical ventilation (Chien et al., 2015). Gene therapy is being investigated with promising results in a mouse model of the disease (Falk et al., 2015; Todd et al., 2015).

Andersen disease, or GSD IV, is due to deficiency of glycogen branching enzyme, expressed in multiple tissues, and may manifest primarily as hepatic or muscular disease, with involvement of the heart and/or the nervous system. Two rare neuromuscular subtypes that present in the newborn period are the fatal perinatal neuromuscular subtype and the congenital neuromuscular subtype. The first presents with fetal akinesia sequence with polyhydramnios, decreased fetal movement, fetal hydrops, and neonatal death or with hypotonia, muscular atrophy, arthrogryposis, and death in the neonatal period from cardiopulmonary failure (Magoulas and El-Hattab, 1993). The second presents with profound hypotonia, respiratory distress requiring mechanical ventilation, dilated cardiomyopathy, and death in early infancy (Escobar et al., 2012). The classic GSD IV subtype is the progressive hepatic subtype. Children are often normal at birth but develop failure to thrive, hypotonia, and potentially progressive liver dysfunction leading to cirrhosis and cardiomyopathy requiring liver and heart transplantation, respectively. Death may result from progressive cardiomyopathy despite liver transplantation. GSD IV is a rare autosomal recessive disorder, and diagnosis is confirmed through DNA sequencing of the GBE1 gene or by detection of abnormal enzyme activity in muscle, liver, or skin fibroblasts.

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Hormonal Regulation of Fuel Metabolism

H. Maurice Goodman , in Basic Medical Endocrinology (Fourth Edition), 2009

Sustained Aerobic Exercise

Glucose taken up from the blood or derived from muscle glycogen is also the most important fuel in the early stages of moderately intense exercise, but with continued effort, dependence on fatty acids increases. Although fat is a more efficient fuel than glucose from a storage point of view, glucose is more efficient than fatty acids from the perspective of oxygen consumption, and yields about 5% more energy per liter of oxygen. Figure 8.16 shows the changes in fuel consumption with time in subjects exercising at 30% of their maximal oxygen consumption. For reasons that are not fully understood, working muscles, even in the trained athlete, cannot derive more than about 70% of their energy from oxidation of fat. Hypoglycemia and exhaustion occur when muscle glycogen is depleted. With sustained exercise, the decline in insulin coupled with an increase in all the counter-regulatory hormones contribute to supplying fat to the working muscles and maximizing gluconeogenesis (Figure 8.17).

Figure 8.16. Changes in sources of fuels utilized during prolonged exercise at 30% of maximal oxygen consumption. (Drawn from the data of Ahlborg, G., Felig, P., Hagenfeldt, L., Hendler, R., and Wahren, J. (1974) Substrate turnover during prolonged exercise in man. Splanchnic and leg metabolism of glucose, free fatty acids, and amino acids J. Clin Invest. 53: 1080–1090.)

Figure 8.17. Changes in concentration of insulin and counterregulatory hormones during prolonged moderate exercise. Values shown are the means obtained for eight young men exercising on a bicycle ergometer at ∼50% of maximum oxygen consumption. (Drawn from data of Davis, S.N., Galassetti, P., Wasserman, D.H., and Tate, D. (2000) Effects of gender on neuroendocrine and metabolic counterregulatory responses to exercise in normal man. J. Clin. Endocrinol. Metab. 85: 224–230.)

Anticipation of exercise may be sufficient to activate the sympathetic nervous system, which is of critical importance, not only for supplying the fuel for the working muscles, but also for making the cardiovascular adjustments that maintain blood flow to carry fuel and oxygen to muscle, gluconeogenic precursors to liver, and heat to sites of dissipation. Insulin secretion is shut down by sympathetic activity. This removes the major inhibitory influence on production of glucose by the liver, glycogen breakdown in muscle, and FFA release from adipocytes. At first glance decreasing insulin secretion might seem deleterious for glucose consumption in muscle. However, the decrease in insulin concentration only decreases glucose uptake by nonworking muscles. Mobilization of GLUT4 and transport of glucose across the sarcolemma is stimulated by AMPK, whose activity is increased by the increased demand of muscular contractions. Glucose metabolism in working muscles therefore is not limited by membrane transport.

Increased hepatic glucose production results primarily from the combined effects of the fall in insulin secretion and the rise in glucagon secretion augmented with some contribution from catecholamines. The contributions of the increased secretion of GH and cortisol to this effect are unlikely to be important initially, but with sustained exercise the contributions of both are likely to increase. Actions of both hormones increase the output of FFA and glycerol and decrease glucose utilization by adipocytes and nonworking muscles. Additionally, the increased cortisol would be expected to increase the expression of gluconeogenic enzymes in the liver.

Glycogen reserves of nonworking muscles may provide an important source of carbohydrate for working muscles during sustained exercise and for restoring muscle glycogen after exercise. Epinephrine and norepinephrine stimulate glycogenolysis in nonworking as well as working muscles. Glucose-6-phosphate produced from glycogen can be broken down completely to carbon dioxide and water in working muscles, but nonworking muscles convert it to pyruvate and lactate, which escape into the blood. Liver then reconverts these 3-carbon acids to glucose, which is returned to the circulation and selectively taken up by the working muscles (Figure 8.18).

Figure 8.18. Postulated interaction between exercising muscle and resting muscle via the Cori cycle. (Redrawn from Ahlborg, G., Wahren, J., and Felig, P. (1986) Splanchnic and peripheral glucose and lactate metabolism during and after prolonged arm exercise. J. Clin. Invest. 77: 690–699.)

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Animal Models of Human Disease

H. Orhan Akman , ... William J. Craigen , in Progress in Molecular Biology and Translational Science, 2011

B Mechanism of Synthesis and Degradation

Different forms of glycogen are found in liver and muscle, with muscle glycogen taking on a structure referred to as β particles, which are visible in the electron microscope as spherical structures that contain up to 60,000 glucose residues per particle. However, in addition to isolated β particles, the liver contains aggregated β particles that appear as rosettes of glycogen and are referred to as α particles. In addition to glucose polymers, liver glycogen also contains glucosamine, which is not found in muscle glycogen. The presence of glucosamine may account for the larger molecular size of liver glycogen particles. The glycogen particles have been referred to as "glycosomes" to indicate that they are distinct organelles, and are composed of both glycogen and the proteins that make up the enzymatic machinery of glycogen synthesis and degradation. The initiation of glycogen synthesis requires a protein "primer" that is termed glycogenin, a uridine diphosphoglucose-requiring glucosyltransferase. The first step in creating glycogen is the autoglucosylation of glycogenin via the two-step attachment of eight glucose molecules to a tyrosine residue of the protein. Glycosylated glycogenin is the primer for the synthesis of glycogen by the sequential action of two enzymes: glycogen synthase and glycogen branching enzyme (GBE). Glycogen synthase and glycogenin exist as a complex in a 1:1 ratio, with one molecule of each per β particle of glycogen. Glycogen synthase adds glucose molecules via ester bonds between the first and fourth carbons of glucose, leading to α-1,4-glucosyl-linked chains. After the addition of 7–11 glucose units, GBE first removes one to four glucose units from the tip of the growing chain and attaches new glucose residues to the adjacent chain via covalent linkage of the sixth to first carbons of glucose, leading to α-1,6-glucosyl-linked branch points. This new branch is now a new primer site for glycogen synthase for the addition of more glucose to the growing chain. This cooperation between the two enzymes allows the glycogen molecule to be a highly branched, soluble molecule.

Similarly, degradation is mediated by the action of two key enzymes: glycogen phosphorylase and glycogen debranching enzyme. Glycogen phosphorylase phosphorylates the terminal glucose molecules of glycogen and catalyzes the sequential cleavage of glucosyl units from α-1,4-glucosyl-linked chains of glycogen, thereby liberating glucose 1-phosphate. Phosphorylase, which exists as a tissue-specific family of isoforms, degrades the glycogen chains until only four glucose units remain before an α-1-6 branch point. Debranching enzyme (amylo-1,6-glucosidase, 4-α-glucanotransferase, AGL), which has two distinct enzymatic activities, first transfers the three glucose residues from the short branch to the end of another branch using its glucosyltransferase activity, where phosphorylase can again degrade the glucosyl chain. Debranching enzyme then hydrolyzes the remaining α-1-6 branch point glucose residue using its amylo-1,6-glucosidase activity, thereby exposing additional glucosyl units to phosphorylase activity. These enzymes are tightly regulated by phosphorylation/dephosphorylation.

Glycogen breakdown is triggered either by a reduction in cellular energy, where hydrolyzed AMP activates cyclic AMP synthesis and, through a signaling cascade, phosphorylase activity is stimulated via phosphorylation, or via hormonal signaling by epinephrine or glucagon. Conversely, phosphorylase is inhibited via dephosphorylation by protein phosphatase 1 in conjunction with a phosphatase termed protein-targeting of glycogen (PTG). Glycogen synthesis is similarly activated by a signal transduction mechanism. Insulin initiates a kinase phosphorylation cascade that activates the glycogen synthase via glycogen synthase kinase (GSK). Glycogen synthase can also be allosterically activated by glucose 6 phosphate (G6P), whereas phosphorylase is inhibited, linking glycogen synthesis or degradation directly to glycolytic metabolism of glucose via the hexokinase step. A role for PTG in glycogen synthase activation via dephosphorylation has also been identified. The overall scheme for the regulation of glycogen metabolism is summarized (Fig. 2).

Fig. 2. Scheme of degradation and synthesis of glycogen; Roman numerals denote glycogenoses due to defects in the following enzymes: 0, glycogen synthase a, liver b, muscle; II, acid maltase; III, debrancher; IV, brancher; V, myophosphorylase; VI, liver phosphorylase; VIII, phosphorylase b kinase; XV, glycogenin a, liver b, muscle. Asterisk indicates there are available animal models for the enzyme defect.

Allosteric regulation of glycogen synthase by G6P is stronger than its inhibition by phosphorylation. In the presence of persistent G6P, such as in the case of a defect in glycolysis, glycogen synthase remains active despite reduced energy levels (Fig. 3). In rare circumstances, the mechanism that senses the energy state of the cell can also be faulty and lead to glycogen accumulation. Activating mutations that cause the inappropriate activation of AMP kinases lead to enhanced glucose uptake, activation of glycogen synthase, and excessive glycogen synthesis. Conversely, deficiency of AMP kinase activity inhibits the degradation of glycogen since it cannot sense the need for energy, again leading to glycogen accumulation due to a failure to degrade it appropriately.

Fig. 3. Defects in malin or laforin cause accumulation of polyglucosan due to hyper phosphorylation of glycogen and its protection from lysosomal targetting. Defects of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy with Wolff–Parkinson–White syndrome.

Glycogen degradation by phosphorylase is not the only mechanism available to meet the demand for glucose. In the first few hours after birth, the neonate depends heavily on the energy from stored glycogen, leading to the degradation of glycogen via lysosomes. This mechanism, when perturbed, leads to a disorder termed glycogen storage disease type II or Pompe disease, in which glycogen accumulates in lysosomes, with the onset of disease varying from the newborn period to elderly adults.

With these mechanisms in mind, we will consider animal models of GSDs in four general categories.

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