In myofibrils, during exercise contraction ADP levels are very high, which favors resynthesis of ATP. Thus, phosphocreatine breaks down to creatine, giving its inorganic phosphate for ATP formation.

This is done by the enzyme creatine phosphokinase which transduces energy from the transport molecule of phosphocreatine to the useful molecule for contraction demands, ATP , an action performed by ATPase in the myofibril.

At the onset of exercise phosphocreatine is broken down to provide ATP for muscle contraction. ATP hydrolysis results in products of ADP and inorganic phosphate. The inorganic phosphate will be transported into the mitochondrial matrix, while the free creatine passes through the outer membrane where it will be resynthesised into PCr.

The antiporter transports the ADP into the matrix, while transporting ATP out. Due to the high concentration of ATP around the mitochondrial creatine kinase , it will convert ATP into PCr which will then move back out into the cells cytoplasm to be converted into ATP by cytoplasmic creatine kinase to be used as energy for muscle contraction.

The idea of the creatine phosphate shuttle was suggested as an explanation for altered blood glucose levels in exercising diabetic patients. It was then proposed that contraction of myofibrils during rigorous exercise freed creatine which imitated the effects of Insulin by consumption of ATP and releasing ADP.

Contents move to sidebar hide. Article Talk. 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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The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The animal study was reviewed and approved by Animal Welfare Committee of Jichi Medical University Protocol No. Conceptualization: ZP and SS. Methodology: ZP and SS. Experiments: ZP and SS. Formal analysis and investigation: ZP and SS.

Discussion: ZP and SS. Writing — original draft: ZP and SS. Writing — review and editing: ZP and SS. Funding acquisition: ZP and SS. Resources: ZP and SS. Supervision: SS. All authors contributed to the article and approved the submitted version. This study was supported by the Japan Society for the Promotion of Science 16H SS , 21K SS and the National Science Foundation of Hunan Province JJ ZP.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

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