Carbohydrate metabolism and exercise -
When very intense short-term exercise begins, all pathways associated with both anaerobic and aerobic ATP provision are activated Box 1. However, the rates of ATP provision from the anaerobic sources, PCr and anaerobic glycolysis are much more rapid than those from aerobic pathways.
PCr is a remarkable fuel source, because only one metabolic reaction is required to provide ATP Box 1. As soon as muscle contractions begin, and ATP is broken down and the concentration of free ADP increases, this reaction moves from left to right Box 1 , and ATP is regenerated in several milliseconds.
Increases in ADP and AMP activate mainly phosphorylase a through allosteric regulation , which breaks down glycogen; the products then combine with inorganic phosphate P i , thus producing glucose 1-phosphate, glucose 6-phosphate and fructose 6-phosphate in the glycolytic pathway. The dual control by local factors associated with muscle contractions and epinephrine 39 , and the combination of covalent and allosteric regulation explain how the flux through phosphorylase can increase from very low at rest to very high during intense exercise in only milliseconds.
The increases in the allosteric regulators ADP, AMP and P i the by-products of ATP breakdown , and the substrate fructose 6-phosphate, activate the regulatory enzyme phosphofructokinase, and flux through the reactions of the glycolytic pathway continues with a net production of three ATP molecules and lactate formation Fig.
Although there are more reactions in the glycolytic pathway than in PCr hydrolysis, the production of ATP through anaerobic glycolysis is also activated in milliseconds. Lactate accumulation can be measured in the muscle after only a 1-s contraction, and the contribution of anaerobic energy from PCr and anaerobic glycolysis is essentially equivalent after 6—10 s of intense exercise 4 , 24 , 40 Fig.
The capacity of the PCr energy store is a function of its resting content ~75 mmol per kg dry muscle and can be mostly depleted in 10—15 s of all-out exercise. The anaerobic glycolytic capacity is approximately threefold higher ~ mmol per kg dry muscle in exercise lasting 30—90 s and is limited not by glycogen availability but instead by increasing intramuscular acidity.
During the transition from rest to intense exercise, the substrate for increased aerobic ATP production is also muscle glycogen, and a small amount of the produced pyruvate is transferred into the mitochondria, where it is used to produce acetyl-CoA and the reducing equivalent NADH in the pyruvate dehydrogenase PDH reaction.
A good example is the enzyme PDH, which is kept in inactive form by resting levels of acetyl-CoA and NADH. The power of these resting regulators is weak compared with that of the heavy hitters in exercise. Instead, AMPK activation during exercise may be functionally more important for the postexercise changes in muscle metabolism and insulin sensitivity, and for mediating some of the key adaptive responses to exercise in skeletal muscle, such as mitochondrial biogenesis and enhanced glucose transporter GLUT 4 expression.
Considerable redundancy and complex spatial and temporal interactions among multiple intramuscular signalling pathways are likely to occur during exercise. In future studies, these approaches should provide new insights into the molecular regulation of skeletal muscle energy metabolism during exercise.
In this situation, there is time to mobilize fat and carbohydrate substrates from sources in the muscle as well as from the adipose tissue and liver Fig. The muscles still rely on anaerobic energy for the initial 1—2 min when transitioning from rest to an aerobic power output, but then aerobic metabolism dominates.
To produce the required ATP, the respiratory or electron-transport chain in the mitochondria requires the following substrates: reducing equivalents in the form of NADH and FADH 2 , free ADP, P i and O 2 Fig.
The respiratory and cardiovascular systems ensure the delivery of O 2 to contracting muscles, and the by-products of ATP utilization in the cytoplasm ADP and P i are transported back into the mitochondria for ATP resynthesis.
The processes that move ATP out of the mitochondria and ADP and P i back into the mitochondria are being intensely studied and appear to be more heavily regulated than previously thought 52 , In the presence of ample O 2 and ADP and P i in the mitochondria, the increase in ADP concentration with exercise is believed to activate the respiratory chain to produce ATP In terms of the metabolic pathways, the tricarboxylic acid TCA cycle in the mitochondria specializes in producing reducing equivalents and accepts acetyl-CoA mainly from carbohydrate and fat and other fuels to do so.
Substrate accumulation and local regulators fine-tune the flux through the dehydrogenases, and a third enzyme, citrate synthase, controls TCA-cycle flux.
Additional NADH is produced both in the glycolytic pathway, after which it is shuttled from the cytoplasm into the mitochondria, and in the PDH reaction, which occurs in the mitochondria.
The transport protein GLUT4 facilitates the influx of glucose into cells, and increases in glucose delivery, secondary to enhanced muscle blood flow, and intramuscular glucose metabolism ensure that the gradient for glucose diffusion is maintained during exercise Translocation of GLUT4 is a fundamental event in exercise-induced muscle glucose uptake, and its regulation has been well studied Transport proteins for fat are also translocated to the muscle membrane mainly plasma membrane fatty acid—binding protein and mitochondrial membranes mainly fatty acid translocase FAT, also known as CD36 , where they transport fatty acids into cells and mitochondria 59 , The fatty acids that are transported into the cytoplasm of the cell and released from IMTG must also be transported across the mitochondrial membranes with the help of the carnitine palmitoyl transferase CPT I system and fat-transport proteins, mainly FAT CD36 61 , Once inside the mitochondria, fat enters the β-oxidation pathway, which produces acetyl-CoA and reducing equivalents NADH and FADH 2 , and the long-chain nature of fatty acids results in generation of large amounts of aerobic ATP Box 1.
In these situations, fuel use shifts to carbohydrate, and reliance on fat is decreased Fig. However, if the endurance event is extended, the liver and skeletal muscle glycogen stores may become exhausted, thereby requiring athletes to slow down.
Researchers have now identified several sites where fat metabolism is downregulated at high aerobic exercise intensities, including decreased fatty acid release from adipose tissue and therefore less fatty acid transport into cells; decreased activation of hormone-sensitive lipase and possibly adipose triglyceride lipase; less IMTG breakdown; and inhibition of CPT I activity as a result of small decreases in muscle pH, decreased CPT I sensitivity to carnitine and possibly low levels of cytoplasmic carnitine-reducing mitochondrial-membrane transport 37 , In many team sports, a high aerobic ability is needed for players to move about the field or playing surface, whereas sprints and anaerobic ATP , as dictated by the game, are added to the contribution of aerobic ATP.
This scenario is repeated many times during a game, and carbohydrate provides most of the aerobic fuel and much of the anaerobic fuel.
Unsurprisingly, almost every regulatory aspect of carbohydrate metabolism is designed for rapid provision of ATP. Carbohydrate is the only fuel that can be used for both aerobic and anaerobic ATP production, and both systems are activated very quickly during transitions from rest to exercise and from one power output to a higher power output.
In addition, the processes that provide fatty acids to the muscles and the pathways that metabolize fat and provide ATP in muscles are slower than the carbohydrate pathways. However, in events requiring long periods of exercise at submaximal power outputs, fat can provide energy for long periods of time and has a much larger ATP-generating capacity than carbohydrate.
Fat oxidation also contributes energy in recovery from exercise or rest periods between activity. Another important aspect of metabolism in stop-and-go sports is the ability to rapidly resynthesize PCr when the exercise intensity falls to low levels or athletes rest.
In these situations, continued aerobic production of ATP fuels the regeneration of PCr such that it can be completely recovered in 60— s ref. This production is extremely important for the ability to repeatedly sprint in stop-and-go or intermittent sports.
Recovery from prolonged sprinting 20—s and sustained high glycolytic flux is slower, because the associated muscle acidity requires minutes, not seconds, to recover and can limit performance 4 , Importantly, other fuels can provide aerobic energy in cells during exercise, including amino acids, acetate, medium-chain triglycerides, and the ketones β-hydroxybutyrate and acetoacetic acid.
Although these fuels can be used to spare the use of fat and carbohydrate in some moderate-intensity exercise situations, they lack the rate of energy provision needed to fuel intense aerobic exercise, because the metabolic machinery for these fuels is not designed for rapid energy provision.
Alternative fuels cannot match carbohydrate in terms of the rate of aerobic energy provision 9 , and these fuels cannot be used to produce anaerobic energy in the absence of oxygen. Sex may have roles in the regulation of skeletal muscle metabolism.
Males and females are often assumed to respond similarly to acute exercise and exercise training, but most of the work cited in this Review involved male participants.
Clear differences exist between males and females—including haemoglobin concentrations, muscle mass and reproductive-hormone levels—and have been shown to affect metabolism and exercise performance, thus making perfect comparisons between males and females very difficult.
The potential sex differences in metabolism are briefly mentioned in Box 3 , and more detailed discussion can be found in a review by Kiens One issue in the study of the regulation of exercise metabolism in skeletal muscle is that much of the available data has been derived from studies on males.
Although the major principles controlling the regulation of metabolism appear to hold true for both females and males, some differences have been noted. Although one might argue that completely matching males and females is impossible when studying metabolism, early work with well-trained track athletes has reported no differences in skeletal muscle enzyme activity, fibre-type composition and fat oxidation between men and women , However, more recent work has reported that a larger percentage of whole-body fuel use is derived from fat in females exercising at the same relative submaximal intensity, and this effect is likely to be related to circulating oestrogen levels , , , , , In addition, supplementation with oestrogen in males decreases carbohydrate oxidation and increases fat oxidation during endurance exercise These results suggest that females may be better suited to endurance exercise than males.
Another area that has been investigated is the effects of menstrual phase and menstrual status on the regulation of skeletal muscle metabolism. Generally, studies examining exercise in the luteal and follicular phases have reported only minor or no changes in fat and carbohydrate metabolism at various exercise intensities , , , Additional work examining the regulation of metabolism in well-trained female participants in both phases of the menstrual cycle, and with varied menstrual cycles, during exercise at the high aerobic and supramaximal intensities commensurate with elite sports, is warranted.
Sports performance is determined by many factors but is ultimately limited by the development of fatigue, such that the athletes with the greatest fatigue resistance often succeed.
However, there can be a fine line between glory and catastrophe, and the same motivation that drives athletes to victory can at times push them beyond their limits. Fatigue is the result of a complex interplay among central neural regulation, neuromuscular function and the various physiological processes that support skeletal muscle performance 1.
It manifests as a decrease in the force or power-producing capacity of skeletal muscle and an inability to maintain the exercise intensity needed for ultimate success. Over the years, considerable interest has been placed on the relative importance of central neural and peripheral muscle factors in the aetiology of fatigue.
All that I am, I am because of my mind. Perhaps the two major interventions used to enhance fatigue resistance are regular training and nutrition 70 , and the interactions between them have been recognized We briefly review the effects of training and nutrition on skeletal muscle energy metabolism and exercise performance, with a focus on substrate availability and metabolic end products.
In relation to dietary supplements, we have limited our discussion to those that have been reasonably investigated for efficacy in human participants Regular physical training is an effective strategy for enhancing fatigue resistance and exercise performance, and many of these adaptations are mediated by changes in muscle metabolism and morphology.
Such training is also associated with the cardiovascular and metabolic benefits often observed with traditional endurance training One hallmark adaptation to endurance exercise training is increased oxygen-transport capacity, as measured by VO 2 max 78 , thus leading to greater fatigue resistance and enhanced exercise performance The other is enhanced skeletal muscle mitochondrial density 80 , a major factor contributing to decreased carbohydrate utilization and oxidation and lactate production 81 , 82 , increased fat oxidation and enhanced endurance exercise performance The capacity for muscle carbohydrate oxidation also increases, thereby enabling maintenance of a higher power output during exercise and enhanced performance Finally, resistance training results in increased strength, neuromuscular function and muscle mass 85 , effects that can be potentiated by nutritional interventions, such as increased dietary protein intake The improved performance is believed to be due to enhanced ATP resynthesis during exercise as a result of increased PCr availability.
Some evidence also indicates that creatine supplementation may increase muscle mass and strength during resistance training No major adverse effects of creatine supplementation have been observed in the short term, but long-term studies are lacking.
Creatine remains one of the most widely used sports-related dietary supplements. The importance of carbohydrate for performance in strenuous exercise has been recognized since the early nineteenth century, and for more than 50 years, fatigue during prolonged strenuous exercise has been associated with muscle glycogen depletion 13 , Muscle glycogen is critical for ATP generation and supply to all the key ATPases involved in excitation—contraction coupling in skeletal muscle Recently, prolonged exercise has been shown to decrease glycogen in rodent brains, thus suggesting the intriguing possibility that brain glycogen depletion may contribute to central neural fatigue Muscle glycogen availability may also be important for high-intensity exercise performance Blood glucose levels decline during prolonged strenuous exercise, because the liver glycogen is depleted, and increased liver gluconeogenesis is unable to generate glucose at a rate sufficient to match skeletal muscle glucose uptake.
Maintenance of blood glucose levels at or slightly above pre-exercise levels by carbohydrate supplementation maintains carbohydrate oxidation, improves muscle energy balance at a time when muscle glycogen levels are decreased and delays fatigue 20 , 97 , Glucose ingestion during exercise has minimal effects on net muscle glycogen utilization 97 , 99 , but increases muscle glucose uptake and markedly decreases liver glucose output , , because the gut provides most glucose to the bloodstream.
Importantly, although carbohydrate ingestion delays fatigue, it does not prevent fatigue, and many factors clearly contribute to fatigue during prolonged strenuous exercise. Because glucose is the key substrate for the brain, central neural fatigue may develop during prolonged exercise as a consequence of hypoglycaemia and decreased cerebral glucose uptake Carbohydrate ingestion exerts its benefit by increasing cerebral glucose uptake and maintaining central neural drive NH 3 can cross the blood—brain barrier and has the potential to affect central neurotransmitter levels and central neural fatigue.
Of note, carbohydrate ingestion attenuates muscle and plasma NH 3 accumulation during exercise , another potential mechanism through which carbohydrate ingestion exerts its ergogenic effect. Enhanced exercise performance has also been observed from simply having carbohydrate in the mouth, an effect that has been linked to activation of brain centres involved in motor control Increased plasma fatty acid availability decreases muscle glycogen utilization and carbohydrate oxidation during exercise , , High-fat diets have also been proposed as a strategy to decrease reliance on carbohydrate and improve endurance performance.
Other studies have demonstrated increased fat oxidation and lower rates of muscle glycogen use and carbohydrate oxidation after adaptation to a short-term high-fat diet, even with restoration of muscle glycogen levels, but no effect on endurance exercise performance , If anything, high-intensity exercise performance is impaired on the high-fat diet , apparently as a result of an inability to fully activate glycogenolysis and PDH during intense exercise Furthermore, a high-fat diet has been shown to impair exercise economy and performance in elite race walkers A related issue with high-fat, low carbohydrate diets is the induction of nutritional ketosis after 2—3 weeks.
However, when this diet is adhered to for 3 weeks, and the concentrations of ketone bodies are elevated, a decrease in performance has been observed in elite race walkers The rationale for following this dietary approach to optimize performance has been called into question Although training on a high-fat diet appears to result in suboptimal adaptations in previously untrained participants , some studies have reported enhanced responses to training with low carbohydrate availability in well-trained participants , Over the years, endurance athletes have commonly undertaken some of their training in a relatively low-carbohydrate state.
However, maintaining an intense training program is difficult without adequate dietary carbohydrate intake Furthermore, given the heavy dependence on carbohydrate during many of the events at the Olympics 9 , the most effective strategy for competition would appear to be one that maximizes carbohydrate availability and utilization.
Nutritional ketosis can also be induced by the acute ingestion of ketone esters, which has been suggested to alter fuel preference and enhance performance The metabolic state induced is different from diet-induced ketosis and has the potential to alter the use of fat and carbohydrate as fuels during exercise.
However, published studies on trained male athletes from at least four independent laboratories to date do not support an increase in performance. Acute ingestion of ketone esters has been found to have no effect on 5-km and km trial performance , , or performance during an incremental cycling ergometer test A further study has reported that ketone ester ingestion decreases performance during a The rate of ketone provision and metabolism in skeletal muscle during high-intensity exercise appears likely to be insufficient to substitute for the rate at which carbohydrate can provide energy.
Early work on the ingestion of high doses of caffeine 6—9 mg caffeine per kg body mass 60 min before exercise has indicated enhanced lipolysis and fat oxidation during exercise, decreased muscle glycogen use and increased endurance performance in some individuals , , These effects appear to be a result of caffeine-induced increases in catecholamines, which increase lipolysis and consequently fatty acid concentrations during the rest period before exercise.
After exercise onset, these circulating fatty acids are quickly taken up by the tissues of the body 10—15 min , fatty acid concentrations return to normal, and no increases in fat oxidation are apparent. Importantly, the ergogenic effects of caffeine have also been reported at lower caffeine doses ~3 mg per kg body mass during exercise and are not associated with increased catecholamine and fatty acid concentrations and other physiological alterations during exercise , This observation suggests that the ergogenic effects are mediated not through metabolic events but through binding to adenosine receptors in the central and peripheral nervous systems.
Caffeine has been proposed to increase self-sustained firing, as well as voluntary activation and maximal force in the central nervous system, and to decrease the sensations associated with force, pain and perceived exertion or effort during exercise in the peripheral nervous system , The ingestion of low doses of caffeine is also associated with fewer or none of the adverse effects reported with high caffeine doses anxiety, jitters, insomnia, inability to focus, gastrointestinal unrest or irritability.
Contemporary caffeine research is focusing on the ergogenic effects of low doses of caffeine ingested before and during exercise in many forms coffee, capsules, gum, bars or gels , and a dose of ~ mg caffeine has been argued to be optimal for exercise performance , The potential of supplementation with l -carnitine has received much interest, because this compound has a major role in moving fatty acids across the mitochondrial membrane and regulating the amount of acetyl-CoA in the mitochondria.
The need for supplemental carnitine assumes that a shortage occurs during exercise, during which fat is used as a fuel.
Although this outcome does not appear to occur during low-intensity and moderate-intensity exercise, free carnitine levels are low in high-intensity exercise and may contribute to the downregulation of fat oxidation at these intensities.
However, oral supplementation with carnitine alone leads to only small increases in plasma carnitine levels and does not increase the muscle carnitine content An insulin level of ~70 mU l —1 is required to promote carnitine uptake by the muscle However, to date, there is no evidence that carnitine supplementation can improve performance during the higher exercise intensities common to endurance sports.
NO is an important bioactive molecule with multiple physiological roles within the body. It is produced from l -arginine via the action of nitric oxide synthase and can also be formed by the nonenzymatic reduction of nitrate and nitrite.
The observation that dietary nitrate decreases the oxygen cost of exercise has stimulated interest in the potential of nitrate, often ingested in the form of beetroot juice, as an ergogenic aid during exercise.
Indeed, several studies have observed enhanced exercise performance associated with lower oxygen cost and increased muscle efficiency after beetroot-juice ingestion , , The effect of nitrate supplementation appears to be less apparent in well-trained athletes , , although results in the literature are varied Dietary nitrate supplementation may have beneficial effects through an improvement in excitation—contraction coupling , , because supplementation with beetroot juice does not alter mitochondrial efficiency in human skeletal muscle , and the results with inorganic nitrate supplementation have been equivocal , Lactate is not thought to have a major negative effect on force and power generation and, as mentioned earlier, is an important metabolic intermediate and signalling molecule.
Of greater importance is the acidosis arising from increased muscle metabolism and strong ion fluxes. In humans, acidosis does not appear to impair maximal isometric-force production, but it does limit the ability to maintain submaximal force output , thus suggesting an effect on energy metabolism and ATP generation Ingestion of oral alkalizers, such as bicarbonate, is often associated with increased high-intensity exercise performance , , partly because of improved energy metabolism and ionic regulation , As previously mentioned, high-intensity exercise training increases muscle buffer capacity 74 , A major determinant of the muscle buffering capacity is carnosine content, which is higher in sprinters and rowers than in marathon runners or untrained individuals Ingestion of β-alanine increases muscle carnosine content and enhances high-intensity exercise performance , During exercise, ROS, such as superoxide anions, hydrogen peroxide and hydroxyl radicals, are produced and have important roles as signalling molecules mediating the acute and chronic responses to exercise However, ROS accumulation at higher levels can negatively affect muscle force and power production and induce fatigue 68 , Exercise training increases the levels of key antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase , and non-enzymatic antioxidants reduced glutathione, β-carotene, and vitamins C and E can counteract the negative effects of ROS.
Whether dietary antioxidant supplementation can improve exercise performance is equivocal , although ingestion of N -acetylcysteine enhances muscle oxidant capacity and attenuates muscle fatigue during prolonged exercise Some reports have suggested that antioxidant supplementation may potentially attenuate skeletal muscle adaptation to regular exercise , , Overall, ROS may have a key role in mediating adaptations to acute and chronic exercise but, when they accumulate during strenuous exercise, may exert fatigue effects that limit exercise performance.
The negative effects of hyperthermia are potentiated by sweating-induced fluid losses and dehydration , particularly decreased skeletal muscle blood flow and increased muscle glycogen utilization during exercise in heat Increased plasma catecholamines and elevated muscle temperatures also accelerate muscle glycogenolysis during exercise in heat , , Strategies to minimize the negative effects of hyperthermia on muscle metabolism and performance include acclimation, pre-exercise cooling and fluid ingestion , , , To meet the increased energy needs of exercise, skeletal muscle has a variety of metabolic pathways that produce ATP both anaerobically requiring no oxygen and aerobically.
These pathways are activated simultaneously from the onset of exercise to precisely meet the demands of a given exercise situation. Although the aerobic pathways are the default, dominant energy-producing pathways during endurance exercise, they require time seconds to minutes to fully activate, and the anaerobic systems rapidly in milliseconds to seconds provide energy to cover what the aerobic system cannot provide.
Anaerobic energy provision is also important in situations of high-intensity exercise, such as sprinting, in which the requirement for energy far exceeds the rate that the aerobic systems can provide.
This situation is common in stop-and-go sports, in which transitions from lower-energy to higher-energy needs are numerous, and provision of both aerobic and anaerobic energy contributes energy for athletic success.
Together, the aerobic energy production using fat and carbohydrate as fuels and the anaerobic energy provision from PCr breakdown and carbohydrate use in the glycolytic pathway permit Olympic athletes to meet the high energy needs of particular events or sports.
The various metabolic pathways are regulated by a range of intramuscular and hormonal signals that influence enzyme activation and substrate availability, thus ensuring that the rate of ATP resynthesis is closely matched to the ATP demands of exercise.
Regular training and various nutritional interventions have been used to enhance fatigue resistance via modulation of substrate availability and the effects of metabolic end products.
The understanding of exercise energy provision, the regulation of metabolism and the use of fat and carbohydrate fuels during exercise has increased over more than years, on the basis of studies using various methods including indirect calorimetry, tissue samples from contracting skeletal muscle, metabolic-tracer sampling, isolated skeletal muscle preparations, and analysis of whole-body and regional arteriovenous blood samples.
However, in virtually all areas of the regulation of fat and carbohydrate metabolism, much remains unknown. The introduction of molecular biology techniques has provided opportunities for further insights into the acute and chronic responses to exercise and their regulation, but even those studies are limited by the ability to repeatedly sample muscle in human participants to fully examine the varied time courses of key events.
The ability to fully translate findings from in vitro experiments and animal studies to exercising humans in competitive settings remains limited.
The field also continues to struggle with measures specific to the various compartments that exist in the cell, and knowledge remains lacking regarding the physical structures and scaffolding inside these compartments, and the communication between proteins and metabolic pathways within compartments.
A clear example of these issues is in studying the events that occur in the mitochondria during exercise. One area that has not advanced as rapidly as needed is the ability to non-invasively measure the fuels, metabolites and proteins in the various important muscle cell compartments that are involved in regulating metabolism during exercise.
Although magnetic resonance spectroscopy has been able to measure certain compounds non-invasively, measuring changes that occur with exercise at the molecular and cellular levels is generally not possible.
Some researchers are investigating exercise metabolism at the whole-body level through a physiological approach, and others are examining the intricacies of cell signalling and molecular changes through a reductionist approach.
New opportunities exist for the integrated use of genomics, proteomics, metabolomics and systems biology approaches in data analyses, which should provide new insights into the molecular regulation of exercise metabolism.
Many questions remain in every area of energy metabolism, the regulation of fat and carbohydrate metabolism during exercise, optimal training interventions and the potential for manipulation of metabolic responses for ergogenic benefits.
Exercise biology will thus continue to be a fruitful research area for many years as researchers seek a greater understanding of the metabolic bases for the athletic successes that will be enjoyed and celebrated during the quadrennial Olympic festival of sport. Hawley, J. Integrative biology of exercise.
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Weis - Fogh , T. Nutrition and Physical Activity Almqvist and Wiksell, Uppsala, Ørngreen, Evelyne Lonsdorfer-Wolf, Stephane Doutreleau, Bernard Geny, Tanya Stojkovic, Monique Piraud, François M. Phosphoglucomutase type 1 PGM1 deficiency is a rare metabolic myopathy in which symptoms are provoked by exercise.
Because the metabolic block is proximal to the entry of glucose into the glycolytic pathway, we hypothesized that iv glucose could improve the exercise intolerance experienced by the patient. Subjects were a year-old man with genetically and biochemically verified PGM1 deficiency and 6 healthy subjects.
Peak work capacity and substrate metabolism during submaximal exercise with and without an iv glucose infusion were measured. Peak work capacity in the patient was normal, as were increases in plasma lactate during peak and submaximal exercise. These results were in contrast to those in the control group, in whom no improvements occurred.
In addition, the patient tended to become hypoglycemic during submaximal exercise. This report characterizes PGM1 deficiency as a mild metabolic myopathy that has dynamic exercise-related symptoms in common with McArdle disease but no second wind phenomenon, thus suggesting that the condition clinically resembles other partial enzymatic defects of glycolysis.
Phosphoglucomutase type 1 PGM1 deficiency glycogen storage disease type XIV is a recently described, rare metabolic myopathy with exercise-related symptoms, mimicking the phenotype of McArdle disease 1 , 2. The enzymatic block in PGM1 deficiency is metabolically similar to that in McArdle disease, because phosphoglucomutase EC 5.
It could therefore be hypothesized that patients with PGM1 deficiency develop a second wind during exercise, like patients with McArdle disease 2 , 4 — 6. The second wind phenomenon has so far been pathognomonic for McArdle disease. It begins after 6 to 8 minutes of aerobic exercise and is signified by a sharp drop in heart rate, accompanied by a subjective feeling that the same exercise feels much easier to perform for the patient 6.
The spontaneous marked improvement in exercise capacity after 6 to 8 minutes of exercise is caused by enhanced uptake and oxidation of glucose and, to a smaller extent, fatty acids 4. Based on this and the location of the metabolic block, we hypothesized that a patient with PGM1 deficiency also could improve exercise tolerance with iv glucose.
We also examined substrate metabolism and hormonal responses to cycle ergometry exercise, using stable isotope methodology and indirect calorimetry. A year-old man body mass index He presented with recurrent cramps evoked by strenuous exercise and had a history suggesting rhabdomyolysis after strenuous physical activity.
The patient underwent exercise tests on 3 consecutive days, and the responses were compared with those of 6 healthy age- and body mass index—matched, sedentary subjects ranging in age from 19 to 61 years mean 37 years.
An incremental cycle ergometer test to exhaustion was performed to determine peak oxygen consumption VO 2peak and peak workload W peak. Plasma lactate concentration was measured at rest and exhaustion. The subjects exercised at a constant workload for 32 minutes, after which the workload was increased in a stepwise manner every other minute until exhaustion.
Blood samples were drawn as shown in Figure 2. The tracer methodology has been described in detail elsewhere 8 , Heart rate and ratings of perceived exertion during exercise.
Open symbols are results from the iv glucose infusion trial, and closed symbols are results from the placebo infusion trial stable isotope infusion. Error bars are the SE. This phase was followed by a stepwise increase in workload until exhaustion.
A and B, heart rate during exercise in the patient and the controls. C and D, ratings of perceived exertion RPE Borg scale. The patient rated exercise at being easier while receiving the iv glucose infusion, whereas none of the controls did.
An iv glucose infusion was given before and during exercise, as described in detail elsewhere Stable isotopes were not infused on this day.
The workload and blood sampling protocol was kept the same as that during the stable isotope trial on the previous day. The principle behind the use of stable isotopes to trace metabolism is infusion of minute amounts of isotopes that do not affect basal metabolism, and hence the trial on day 2 was used as a placebo test to assess the effect of the glucose infusion.
Informed consent was obtained from all subjects before inclusion in the study. The study was approved by the Regional Committee on Biomedical Research Ethics of Copenhagen approval H-D and was performed according to the ethical standards of the Declaration of Helsinki.
Results are described qualitatively and with descriptive statistics and are reported as means ± SE. Plasma lactate increased from rest to exhaustion in the patient 1. No second wind phenomenon was observed, and the patient did not report any exercise-related symptoms.
Despite this shift in metabolism toward fat use, the oxidation rate of carbohydrates during exercise was high, and plasma lactate levels increased Figure 1 , C and D , indicating a significant glycolytic flux during exercise. In the patient, plasma glucose levels declined during exercise and almost reached hypoglycemic levels Figure 1 E.
Substrate oxidation rates and lactate and glucose concentrations during exercise. This phase was followed by a stepwise increase in workload every other minute until exhaustion, when a final blood sample was drawn.
Time of exhaustion was arbitrarily set to 40 minutes. A, Palmitate oxidation rates ROX. B, Rate of appearance Ra of palmitate.
C, Carbohydrate oxidation rates during exercise. D and E, Lactate concentrations D and glucose concentrations E measured during the stable isotope infusion trial. Plasma lactate levels increased in the patient, but plasma glucose levels declined, even at time of exhaustion 3. These results were in contrast to those of the control subjects, in whom the glucose levels remained stable and finally increased at the time of exhaustion all subjects.
F, Glucose concentrations during the iv glucose infusion trial. Plasma glucose levels declined more rapidly in the patient, and hypoglycemia was barely prevented by the infusion, indicating an increased uptake.
In the patient, the iv glucose infusion caused a reduction in heart rate, which was accompanied by a reduction in ratings of perceived exertion during constant load exercise Figure 2. In contrast, the glucose infusion did not influence exercise tolerance in any of the control subjects.
In further support of a beneficial effect of iv glucose, the patient could exercise longer and reached a higher W peak than with a placebo Figure 2. The plasma glucose concentration tended to drop faster and more during exercise in the patient than in the control subjects, indicating an increased uptake Figure 1 F.
Plasma lactate concentrations were similar in both groups. We examined substrate metabolism and the response to an iv glucose infusion during cycle ergometry exercise in a patient with genetically proven PGM1 deficiency.
He had a normal peak work capacity and no second wind phenomenon, suggesting that the condition clinically resembles a number of other glycogen storage diseases such as phosphoglycerate mutase and kinase deficiencies and lactate dehydrogenase deficiency 12 , However, unlike these conditions, iv glucose infusion improved the capacity for work.
This response to glucose infusion has so far only been observed in patients with McArdle disease, pointing to a higher reliance on hepatic glucose to feed contracting muscle to compensate for the mildly affected muscle glycogenolysis 4. In support of a partially reduced capacity for skeletal muscle glycogenolysis, the PGM1-deficient patient had a shift in metabolism toward an increase in fatty acid oxidation.
This may be compensatory for a reduced capacity for glycogenolysis during exercise and is also seen in McArdle disease Glycogenolysis is partially preserved in PGM1 deficiency.
In addition, in contrast to the effects of McArdle disease, capacity for work was normal and lactate production during exercise was normal. Several mechanisms may explain these differences.
One factor is the expression of the PGM2 isoform of phosphoglucomutase in skeletal muscle. Liver glycogenolysis is unaffected in McArdle disease, as a consequence of the expression of different isoforms of glycogen phosphorylase in these two tissues.
Blood glucose levels are maintained above hypoglycemic levels, but, as we found in the PGM1-deficient patient, blood glucose levels may gradually decline during exercise because of the large increase in skeletal muscle uptake and use of blood glucose 4.
Our present knowledge of carbohydrate metabolism during exercise Carbohydrate metabolism and exercise summarized in many Carbohydrate metabolism and exercise and Immune-boosting fruits review exercis [13, 17, 21, 29]. Exrrcise presentation Carrbohydrate therefore be limited to a discussion of some of the many unsolved questions which still exist within this field. More precisely I will use results from recent studies to shed some light on three specific problems. These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves. Carbohydrates Carbohydrxte the preferred substrate for contracting skeletal muscles during metablism exercise Science-backed weight control Carbohydrate metabolism and exercise also readily utilized during moderate intensity exercise. This use of carbohydrates during HbAc monitoring frequency activity Carbohydrate metabolism and exercise played exerccise important role during the survival of early Homo sapiens, and genes and traits exercies physical activity, carbohydrate metabolism, and energy storage have undoubtedly been selected throughout evolution. In contrast to the life of early H. sapiens, modern lifestyles are predominantly sedentary. As a result, intake of excessive amounts of carbohydrates due to the easy and continuous accessibility to modern high-energy food and drinks has not only become unnecessary but also led to metabolic diseases in the face of physical inactivity. A resulting metabolic disease is type 2 diabetes, a complex endocrine disorder characterized by abnormally high concentrations of circulating glucose. This disease now affects millions of people worldwide.
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