Notes on Exercise Metabolism (Nature Metabolism Review, 2020)

Overview of exercise metabolism

• Olympic-level athletic performance depends on a complex interplay of biological, mental and environmental factors, with ATP availability tightly linked to skeletal muscle contraction across events from seconds (sprint) to hours (endurance).
• Intramuscular ATP stores are small (~5 mmol ATP per kg wet muscle) and cannot sustain prolonged activity; thus multiple ATP-resynthesis pathways are activated in parallel to meet demand.
• For all-out, maximal exercise at a power output of about 900 W (≈300% VO2 max), the estimated ATP utilization rate is 3.7\;\text{mmol ATP kg}^{-1}\text{ s}^{-1}, and exercise could last <2 s if ATP were the sole source.
• For submaximal exercise at ~200 W (≈75% VO2 max), ATP utilization is about 0.4\;\text{mmol ATP kg}^{-1}\text{ s}^{-1}, lasting ≈15 s before other pathways dominate.
• Therefore, other metabolic pathways must be activated: substrate-level phosphorylation (anaerobic) and oxidative phosphorylation (aerobic).
• Oxidative metabolism relies on respiratory and cardiovascular systems to deliver oxygen to contracting muscle and on metabolism of carbohydrate and fat to provide reducing equivalents (NADH, FADH2).
• Relative contributions of anaerobic vs aerobic pathways differ by intensity and duration; anaerobic pathways have higher power but lower total ATP yield, while aerobic pathways have higher capacity but lower instantaneous power.
• For carbohydrate vs fat, oxidation power differs: carbohydrate oxidation has higher power output but lower capacity than fat oxidation; this contributes to power decline when carbohydrate is depleted in prolonged exercise.
• The Review also discusses potential strategies to target metabolism for ergogenic benefits and emphasizes regulatory mechanisms that match ATP supply to demand.

Substrates and fuels for exercise

• Major intramuscular and extramuscular substrates: muscle glycogen, blood glucose (from liver glycogenolysis, gluconeogenesis, and gut carbohydrate ingestion), and fatty acids from intramuscular triglyceride (IMTG) stores and adipose tissue triglycerides.
• The energy contribution from these stores depends on exercise intensity and duration (Fig. 2 in the article).
• Carbohydrate oxidation (particularly muscle glycogen) dominates at higher intensities; fat oxidation is more important at lower intensities.
• Maximal fat oxidation occurs at ~60$-$65\% \, VO_2\max.
• IMTG oxidation is greatest early in exercise and declines with duration as glucose and fatty acid uptake/oxidation rise.
• Liver glucose output increases with exercise via liver glycogenolysis and gluconeogenesis; during prolonged exercise, liver output may fall behind muscle uptake, potentially causing hypoglycemia unless carbohydrates are ingested to maintain blood glucose.
• Adipose tissue lipolysis increases plasma free fatty acid (FFA) availability to support oxidation, but lipolysis can exceed uptake and oxidation, leading to rising plasma FFA levels.
• Inhibition of adipose lipolysis shifts reliance toward muscle glycogen and IMTG with little effect on muscle glucose uptake.
• The importance of IMTG as a fuel source is debated and may depend on training status, sex, fiber type, and resting IMTG stores, but it appears important in trained individuals.
• Glycolysis accelerates during high-intensity exercise and produces lactate, which accumulates in both muscle and blood, especially at higher intensities.
• Lactate is now seen as a substrate for oxidative metabolism, gluconeogenesis and glycogen synthesis, and as a signaling molecule mediating exercise adaptations and interorgan communication.
• Glycerol and alanine are released from contracting muscle and adipose tissue and can serve as gluconeogenic precursors for the liver during exercise.
• Protein turnover increases during exercise; amino acids (notably branched-chain AAs) can be oxidized, but their contribution to ATP production is relatively small; under low carbohydrate availability, amino acid oxidation increases, whereas endurance training reduces leucine oxidation.
• Postexercise increases in myofibrillar and mitochondrial protein synthesis underlie adaptations to both endurance and resistance training.

Regulation of exercise metabolism: general principles

• At the onset of exercise, metabolic rate can surge more than 100-fold, requiring rapid ATP provision and tight maintenance of muscle ATP content.
• Regulation involves Ca2+ signals, energy charge (ADP, AMP, Pi), epinephrine, NO, ROS, temperature, tension, and other factors; many kinases and signaling cascades are engaged.
• A central concept is dual-stage control: gross control by Ca2+ (and epinephrine) rapidly activates key regulatory enzymes; fine-tuning control then adjusts ATP production to actual demand via feedback from ADP, AMP, Pi, etc. (Box 2).
• Ca2+ released from the sarcoplasmic reticulum activates enzymes that regulate carbohydrate and fat metabolism as contraction proceeds; this constitutes an early feed-forward “heavy hitter” control.
• AMPK senses energy status (glycogen and energy charge) and is implicated in postexercise metabolic regulation and adaptations; during exercise its role in acute GLUT4 trafficking and fat oxidation is less clear, but it is important for postexercise insulin sensitivity and mitochondrial biogenesis.
• Phosphoproteomic studies have identified thousands of exercise-regulated phosphosites across hundreds of proteins, highlighting complexity and redundancy in signaling networks.
• Coadministration of Ca2+ signals with β-adrenergic stimulation in cell models recapitulates exercise-like phosphoproteomic signatures, underscoring the roles of Ca2+ and epinephrine in exercise signaling.
• Future directions emphasize integrative omics and systems biology to understand acute and chronic regulation of skeletal muscle energy metabolism.

Aerobic vs anaerobic metabolism and substrate flux

• Aerobic metabolism dominates in endurance exercise at intensities below ~100% VO2 max, with energy supplied by fats and carbohydrates from within the muscle and from outside (adipose tissue and liver).
• During the initial 1–2 minutes of aerobic exercise, there is still some contribution from anaerobic sources, but aerobic metabolism rapidly takes over as duration increases.
• The substrates for aerobic ATP production include reducing equivalents (NADH, FADH2), ADP, Pi, and O2; delivery systems (blood flow, capillarization) are essential for substrate supply.
• Liver glycogen output (200–400 kcal) and muscle glycogen (1,000–3,000 kcal) are major carbohydrate sources; IMTG supplies (2,000–3,000 kcal) and plasma FFAs are major fat sources.
• In endurance events, carbohydrate often supplies most of the energy, with fat oxidation contributing a substantial portion, especially at moderate intensities.
• Fat oxidation provides large energy capacity but slower kinetics due to transport and beta-oxidation steps; carbohydrate provides rapid ATP through glycolysis and PDH-driven oxidation and is critical for high-intensity efforts.
• The transition from rest to exercise involves rapid activation of glycolysis and PDH, accelerated glycogen breakdown, and mobilization of intramuscular and circulating substrates; PDH is activated by Ca2+ and pyruvate, balancing acetyl-CoA and NADH levels.
• PDH regulation illustrates dual-stage control: resting PDH is inhibited by high acetyl-CoA and NADH; during exercise, Ca2+ and pyruvate activate PDH, sustaining glycolytic throughput despite inhibitory signals.
• NO and ROS signaling contribute to metabolic regulation and GLUT4 translocation, though their precise roles in whole-body glucose uptake during exercise are nuanced.

Glycolysis, PDH, and metabolic control during exercise

• The glycolytic flux is rapidly increased during transition to exercise, with ADP, AMP and Pi acting as allosteric activators of phosphofructokinase (PFK).
• Glycolysis generates ATP rapidly but produces lactate when oxygen delivery cannot meet the rate of NADH oxidation; lactate accumulation serves as an important metabolic substrate and signaling molecule.
• The NADH produced in glycolysis and PDH is shuttled into mitochondria to fuel aerobic ATP production; acetyl-CoA production from pyruvate by PDH links glycolysis to the TCA cycle.
• The citrate synthase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase steps of the TCA cycle are activated by mitochondrial Ca2+ during aerobic exercise, increasing flux through the cycle.
• The rate of glycolysis and acetyl-CoA supply to the TCA cycle is adjusted by local factors and regulatory enzymes; Ca2+ and epinephrine provide early activation, while ADP, AMP and Pi provide feedback for fine-tuning.

Transport, signaling, and substrate handling during exercise

• Glucose uptake is driven by GLUT4 translocation to the sarcolemma; a combination of Ca2+-mediated signaling, adiponectin/NO signaling, Rac1, and AMPK pathways contribute to regulation, with Rac1 emerging as a key player in exercise-stimulated glucose uptake.
• Fat uptake and oxidation involve transporters such as fatty acid–binding proteins (FABPpm), fatty acid translocase (FAT/CD36) and CPT I, which mediate mitochondrial import and beta-oxidation.
• The transport of fatty acids into mitochondria requires carnitine palmitoyltransferase I (CPT I) and related transport systems; high-intensity exercise can down-regulate CPT I activity via pH changes and other regulators, limiting fat oxidation at high intensities.
• Fatty acids released from IMTG are transported to mitochondria for beta-oxidation, generating acetyl-CoA and reducing equivalents; mitochondrial beta-oxidation yields substantial ATP, particularly during long-duration exercise at moderate intensities.
• Lactate produced during high-intensity exercise can be transported to other tissues (e.g., liver, heart, brain) for gluconeogenesis or oxidation, illustrating interorgan lactate exchange and the lactate shuttle concept.
• Amino acids contribute modestly to ATP production, with increased oxidation under low carbohydrate availability; endurance training generally reduces leucine oxidation.
• Muscle glycogen breakdown, liver glucose output, and plasma glucose uptake are coordinated to maintain blood glucose and muscle energy supply during prolonged exercise.

Fuel utilization patterns across exercise intensities (factual anchors)

• Maximal fat oxidation occurs at roughly 60–65% VO2 max.
• During high-intensity exercise, carbohydrate becomes the dominant fuel source, with muscle glycogen and liver glucose usage supporting both anaerobic and aerobic metabolism.
• In endurance events lasting several minutes to hours, carbohydrate and fat oxidation together provide the majority of ATP, with carbohydrate playing a leading role at high intensities and fat providing substantial energy during longer, submaximal efforts.
• The relative contributions of fuel sources shift over time: early stages rely more on IMTG and glycogen; later stages see increased plasma glucose uptake and liver glucose output, with liver output potentially lagging muscle uptake if carbohydrate intake is insufficient.
• In planning nutrition for performance, it's important to consider that carbohydrate ingestion delays fatigue by maintaining blood glucose and supporting brain energy supply, while fat oxidation becomes more prominent when carbohydrate availability is limited.

Phosphocreatine (PCr) resynthesis and recovery dynamics

• PCr resynthesis is rapid and supports repeated high-intensity efforts in stop-and-go sports.
• In recovery, continued aerobic ATP production fuels PCr resynthesis, typically completing within 60–120 s to fully restore PCr stores after sprint bouts, enabling repeated sprints.
• Recovery from prolonged sprinting and high glycolytic flux is slowed by acidosis, requiring more time for restoration of metabolic balance.

Other fuels and alternative energy substrates

• In addition to carbohydrate and fat, other fuels can contribute to aerobic energy during exercise, including certain amino acids, acetate, medium-chain triglycerides, and ketones (β-hydroxybutyrate, acetoacetate).
• These fuels are generally less capable of providing rapid energy for high-intensity exercise due to slower metabolism or lower storage levels, and they cannot support anaerobic energy production in the absence of oxygen.

Sex differences in exercise metabolism (Box 3)

• Most data come from male participants; significant sex differences exist in several aspects of metabolism that can affect performance.
• Relative to men, females may rely more on fat oxidation during submaximal exercise, possibly due to circulating estrogen levels and higher IMTG stores in type I fibers.
• Females may have a higher proportion of type I fibers and lower glycolytic capacity, affecting substrate selection and endurance performance.
• Estrogen supplementation in men can shift substrate use toward greater fat oxidation and reduced carbohydrate oxidation during endurance exercise.
• Men and women may differ in menstrual phase effects on fat and carbohydrate metabolism; however, evidence is mixed and more research in well-trained female participants is needed across menstrual phases.

Targeting metabolism for ergogenic benefit: general considerations

• Fatigue resistance is a key determinant of performance; interventions aim to modulate substrate availability and end-product effects on muscle.
• Training and nutrition interact to enhance fatigue resistance and performance through multiple pathways; practical strategies are evaluated in human participants.

Ergogenic interventions and their mechanisms

• Creatine supplementation
  • Increases total skeletal muscle creatine content by ~20–25% and PCr by ~10–15% with short-term use, enhancing ATP resynthesis during repeated high-intensity efforts and potentially increasing muscle mass and strength with resistance training.
  • Typical short-term use has few adverse effects; long-term data are limited.
• Carbohydrate loading and glycogen availability
  • Carbohydrate availability is crucial for endurance performance; glycogen depletion is a key fatigue factor in prolonged strenuous exercise.
  • Carbohydrate loading before events (>60–90 min) increases muscle glycogen and endurance capacity; muscle glycogen availability also supports high-intensity work.
  • Blood glucose tends to fall during prolonged exercise as liver glycogen becomes depleted; carbohydrate ingestion maintains oxidation and delays fatigue by supporting cerebral glucose delivery and central drive.
  • Ingested carbohydrate reduces endogenous hepatic glucose production during exercise, as gut-delivered glucose maintains blood glucose and muscle uptake.
  • Central fatigue is linked to brain glucose availability; carbohydrate feeding can mitigate CNS fatigue by maintaining cerebral glucose delivery and drive.
• Ketone esters and ketogenic diets
  • Ketone esters can induce nutritional ketosis and shift fuel preference, but studies in trained athletes largely do not show performance benefits; some trials show neutral or even negative effects on time-trial performance.
  • Ketone-based ketosis from long-term ketogenic diets can reduce carbohydrate availability and may impair high-intensity performance; ketosis effects depend on training status and the specific metabolic context.
  • Acute exogenous ketone supplementation has not consistently improved performance in endurance tasks.
• Caffeine
  • Acute caffeine ingestion (commonly 3–6 mg/kg body mass) can enhance endurance performance and may improve high-intensity efforts; effects may be greater with higher lactate thresholds and in certain individuals.
  • Mechanisms include central nervous system effects (increased motor drive and reduced perceived exertion) and peripheral metabolic effects (increased lipolysis) primarily at higher doses; lower doses (≈200 mg) can also be ergogenic, potentially via central mechanisms rather than metabolic changes.
• Carnitine supplementation
  • Oral carnitine with carbohydrate can increase muscle carnitine content and affect fuel metabolism, but evidence for improved high-intensity or endurance performance is inconclusive.
  • A threshold insulin response is needed to promote muscle carnitine uptake; long-term carnitine loading with carbohydrate has shown modest metabolic changes, but clear performance benefits are not established.
• Nitrate and beetroot juice
  • Dietary nitrate can reduce the oxygen cost of exercise and improve muscle efficiency in some contexts, particularly at submaximal intensities; results in elite athletes are mixed.
  • Potential mechanisms include improved excitation–contraction coupling and improved efficiency rather than direct mitochondrial enhancement; results with inorganic nitrate are less consistent.
• Alkalosis and buffering strategies
  • Exercise-induced acidosis (high H+, lactate, Pi) can impair submaximal force; buffering strategies (oral bicarbonate) can improve high-intensity performance by improving muscle acid-base balance and ionic regulation.
  • Beta-alanine supplementation increases muscle carnosine content, which can buffer H+ and improve performance in high-intensity contractions.
• Antioxidants
  • ROS participate in signaling and adaptation to exercise, but excessive ROS can impair force and contribute to fatigue.
  • Regular training upregulates endogenous antioxidant enzymes; exogenous antioxidant supplementation remains controversial, as it may blunt training adaptations in some contexts, though some supplements (e.g., N-acetylcysteine) can reduce fatigue markers in prolonged exercise.
• Hyperthermia and heat management
  • Heat production during exercise is largely dissipated by sweating; hyperthermia can impair central drive, cardiovascular function and muscle metabolism.
  • Environmental heat and dehydration exacerbate fatigue; strategies include acclimation, pre-cooling and fluid replacement.

Training, recovery, and practical implications

• Regular training improves fatigue resistance and performance via multiple adaptations:
  • Endurance training increases VO2 max and skeletal muscle mitochondrial density, reducing carbohydrate use and lactate production, and increasing fat oxidation efficiency.
  • Endurance training also enhances carbohydrate oxidation capacity, enabling higher sustained power output during submaximal exercise.
  • Resistance training improves strength and neuromuscular function; this can be complemented by nutritional strategies to enhance adaptations.
  • High-intensity interval training enhances anaerobic energy capacity, buffering capacity, and ionic regulation, contributing to improved performance and metabolic health.
• Training- and nutrition-driven fatigue resistance are interdependent and are a major focus of sports science.

Practical notes on figures, boxes, and references from the transcript

• Box 1 (Energy metabolism in skeletal muscle): outlines major ATP utilization and resynthesis pathways, including PCr, glycolysis, and oxidative phosphorylation, with schematic notes on substrate-level phosphorylation and ATP yields.
• Box 2 (Metabolic control during exercise): explains dual-stage control by Ca2+ and metabolic signaling that rapidly activates PDH and other enzymes at exercise onset, followed by fine-tuning via ADP/AMP/Pi feedback.
• Box 3 (Sex differences in exercise metabolism): highlights observed differences in substrate use and hormonal influences between men and women, including effects of estrogen on fat oxidation and IMTG usage; notes the need for more research in well-trained female participants across menstrual phases.
• Figures referenced in the text (Fig. 1–4) illustrate the distribution of ATP turnover among PCr, glycolysis, and oxidative phosphorylation during intense exercise, substrate contributions to oxidative metabolism, relative fuel contributions across intensities, and the major metabolic pathways and regulatory nodes during exercise.
• Representative numerical anchors and units include:
  • Muscle ATP stores: \approx 5\ \text{mmol ATP kg}^{-1}\text{ wet muscle}
  • Resting PCr content: approximately 75\ \text{mmol kg}^{-1}\text{ dry muscle}
  • Muscle glycogen stores: 1{,}000$-$3{,}000\ \text{kcal}; liver glycogen: 200$-$400\ \text{kcal}
  • Maximal fat oxidation around 60$-$65\% VO$_2$ max
  • ATP yield examples in Box 1: oxidative phosphorylation and fatty acid oxidation with large ATP outputs (e.g., \text{Glucose} + 6\ O2 + 36\ ADP \rightarrow 6\ CO2 + 6\ H2O + 36\ ATP; \text{Palmitate} + 23\ O2 + 130\ ADP \rightarrow 16\ CO2 + 16\ H2O + 130\ ATP)
• Several key enzymes and transporters mentioned:
  • Glycogen phosphorylase; PDH (pyruvate dehydrogenase); phosphorylase kinase; PFK (phosphofructokinase)
  • GLUT4 (glucose transporter) translocation and regulators such as Rac1
  • CPT I (carnitine palmitoyltransferase I) and FAT/CD36 (fatty acid transporter)
  • MCT (monocarboxylate transporter) for lactate transport
• The Review emphasizes unresolved questions and methodological challenges, such as noninvasive measurement of fuels and metabolites within muscle compartments, and the integration of omics approaches to understand molecular regulation of exercise metabolism.

Summary takeaway points

• The body relies on both anaerobic and aerobic pathways to meet the rapidly changing energy demands of exercise; ATP supply is carefully matched to demand via dual-stage regulatory systems centered on Ca2+, energy charge signals, and hormonal inputs.
• Fuel selection shifts with intensity and duration: carbohydrates dominate at higher intensities, fats contribute more at lower intensities, with IMTG playing a variable role depending on training and fiber type.
• Lactate is not merely a waste product but an important metabolic substrate and signaling molecule linked to adaptations in skeletal muscle and interorgan communication.
• Ergogenic strategies (creatine, carbohydrate strategies, caffeine, nitrate, buffering agents, and others) can influence performance through multiple mechanisms, but effectiveness varies with context, dose, and individual response; long-term dietary patterns (e.g., high-fat ketogenic approaches) may impair high-intensity performance in some athletes.
• Ongoing research aims to integrate molecular signaling, substrate transport, and whole-body physiology to optimize training, nutrition, and recovery for athletic performance.