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Cited by 414Diet and metabolism studiesMuscle metabolism and nutritionSports Performance and Training

Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation

Open access
Evans, Mark, Cogan, Karl E., Egan, Brendan·2017·The Journal of Physiology
DOI 10.1113/jp273185PMC PMC5407977
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Abstract

Optimising training and performance through nutrition strategies is central to supporting elite sportspeople, much of which has focused on manipulating the relative intake of carbohydrate and fat and their contributions as fuels for energy provision. The ketone bodies, namely acetoacetate, acetone and β‐hydroxybutyrate (βHB), are produced in the liver during conditions of reduced carbohydrate availability and serve as an alternative fuel source for peripheral tissues including brain, heart and skeletal muscle. Ketone bodies are oxidised as a fuel source during exercise, are markedly elevated during the post‐exercise recovery period, and the ability to utilise ketone bodies is higher in exercise‐trained skeletal muscle. The metabolic actions of ketone bodies can alter fuel selection through attenuating glucose utilisation in peripheral tissues, anti‐lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. Moreover, ketone bodies can act as signalling metabolites, with βHB acting as an inhibitor of histone deacetylases, an important regulator of the adaptive response to exercise in skeletal muscle. Recent development of ketone esters facilitates acute ingestion of βHB that results in nutritional ketosis without necessitating restrictive dietary practices. Initial reports suggest this strategy alters the metabolic response to exercise and improves exercise performance, while other lines of evidence suggest roles in recovery from exercise. The present review focuses on the physiology of ketone bodies during and after exercise and in response to training, with specific interest in exploring the physiological basis for exogenous ketone supplementation and potential benefits for performance and recovery in athletes. image

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TL;DR

This review argues that ketone bodies are oxidizable fuels and signaling metabolites whose utilization rises during exercise and with training, and that exogenous ketone esters can produce acute nutritional ketosis and alter fuel selection. It concludes that preliminary evidence suggests performance and recovery benefits in trained athletes, but optimal dosing, safety, and sport-specific effects remain unresolved.

Key findings

  • Ketone bodies are produced in the liver during reduced carbohydrate availability; plasma [KB] is <0.1 mm postprandial, with hyperketonaemia defined as >0.2 mm. Skeletal muscle accounts for the highest fraction of total KB metabolism at rest because it is ∼40% of adult body mass, but KBs normally contribute <5% to muscle energy, rising to ∼10% after an overnight fast, 20–50% after 72 h fasting, and declining to ∼15% after 24 days of starvation; saturation likely occurs between 1 and 2 mm.
  • Exercise increases KB disposal into human skeletal muscle as much as fivefold, and metabolic clearance rate rises by 50–75% during low-to-moderate exercise after an overnight fast. However, when ketonaemia exceeds 2.5 mm after >72 h fasting, the exercise-induced rise in MCR is abolished; exogenous AcAc infusion achieving ∼6 mm [KB] (βHB ∼3.5 mm, AcAc ∼2.5 mm) contributed only 2% to energy provision over 2 h but prevented the exercise rise in plasma lactate.
  • Ketone monoester ingestion at 573 mg (kg BM)−1 produced [βHB] of ∼3 mm after 10 min and ∼6 mm after 30 min. During 45 min exercise at 40% or 75% Wmax, [βHB] was ∼2 and 3 mm lower, respectively, and βHB oxidation contributed 18% and 16% of oxygen consumption; KE + CHO improved 30 min time-trial performance by 2% (411±162 m; mean ± SEM, n = 8) versus isocaloric CHO and blunted plasma lactate by ∼2–3 mm (∼50% reduction).
  • Training increases ketolytic capacity: in rodents, 12 weeks treadmill running raised BDH activity almost threefold in type I fibres and sixfold in type IIA fibres, with OXCT and ACAT also higher; βHB inhibits HDACs at physiologically relevant 1–4 mm concentrations, but this remains to be confirmed in skeletal muscle.

Methods

  • Narrative review; no primary experimental data were collected. It synthesizes human and rodent literature on ketogenesis, ketolysis, exercise metabolism, training adaptation, and exogenous ketone supplementation.
  • Evidence discussed includes tracer/arteriovenous studies, fasting and ketogenic-diet models, ketone salt or ester infusion/ingestion, and recent ketone monoester exercise trials such as Cox et al. (2016).
  • Main analysis is qualitative synthesis; no systematic search strategy, meta-analysis, or formal risk-of-bias assessment is stated.

Limitations

  • The authors state that much more research is needed, that only one peer-reviewed paper has examined exercise metabolism, performance, and nutritional ketosis, and that data are preliminary; optimal βHB range is only speculated as 1–3 mm, and side effects such as gastrointestinal distress and possible acidosis require caution.
  • The authors note that HDAC inhibition by βHB remains to be confirmed in skeletal muscle, and that direct comparisons between fasting-induced and exogenous ketosis are difficult because of differing hormonal and metabolic milieus.
  • Evident from the text: many mechanistic and training findings are from rodents, and some human recovery evidence is from a preliminary abstract (Holdsworth et al. 2016); the performance evidence cited is limited to a small time-trial study (n = 8) in trained cyclists.

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Registry

Crossref · 10.1113/jp273185

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation
    § Introduction

    Ketone bodies are utilised by working muscle during exercise.

    “KBs are utilised by working muscle during exercise (Fery & Balasse, 1986, 1988)”
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    § Introduction

    Exogenous ketones are ingested in the form of βHB salts or ketone esters to produce acute (∼0.5 to 6 h) nutritional ketosis.

    “exogenous ketones are ingested in the form of βHB salts or ketone esters to produce acute (∼0.5 to 6 h) nutritional ketosis (Clarke et al. 2012; Kesl et al. 2016)”
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  • Premisecitation
    § Introduction

    In rats, enzymatic activities of BDH, OXCT and ACAT are highest in type I fibres, intermediate in type IIA fibres, and lowest in type IIB fibres.

    “enzymatic activities of BDH, OXCT and ACAT are all highest in type I fibres, intermediate in type IIA fibres, and lowest in type IIB fibres of rats (Winder et al. 1974).”
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  • Premisecitation
    § Introduction

    Skeletal muscle is a major site of ketolysis at rest.

    “established that skeletal muscle is a major site of ketolysis at rest”
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    § Introduction

    Skeletal muscle demonstrates saturation kinetics for the KB concentration-oxidation relationship, with saturation likely between 1 and 2 mM.

    “Thus, skeletal muscle demonstrates saturation kinetics for the KB concentration–oxidation relationship, with saturation likely between 1 and 2 mm as demonstrated by fasting of various durations (compiled in Balasse & Fery, 1989) or step‐wise βHB infusion (Mikkelsen et al. 2015).”
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    Premisecitation
    § Introduction

    MCT1 protein expression is highest in type I fibres, poorly expressed in type II fibres, and correlates well with muscle oxidative capacity.

    “MCT1 protein expression is highest in type I fibres, poorly expressed in type II fibres, and correlates well with muscle oxidative capacity (Bonen, 2001).”
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    Premisecitation
    § Introduction

    A recent report provides the first evidence that acute nutritional ketosis achieved by ketone ester ingestion alters the metabolic response to exercise and enhances exercise performance.

    “a recent report provides the first evidence for acute nutritional ketosis achieved by ketone ester ingestion to alter the metabolic response to exercise and enhance exercise performance (Cox et al. 2016)”
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    • cites Cox et al. 2016

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    Premisecitation
    § Introduction

    In rats after 12 weeks of treadmill running, OXCT activity was 26% higher in type I fibres and approximately twofold higher in type IIA and IIB fibres compared to sedentary rats.

    “OXCT activity was 26% higher in type I, and approximately twofold higher in type IIA and IIB fibres”
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    Premisecitation
    § Introduction

    The relationship between ketone oxidation and [KB] is curvilinear; contribution to energy provision in skeletal muscle rises to ∼10% after an overnight fast, 20% to 50% after 72 h of fasting, but declines to ∼15% after 24 days of starvation.

    “The relationship between ketone oxidation and [KB] is curvilinear such that contribution to energy provision in skeletal muscle rises to ∼10% after an overnight fast (Hagenfeldt & Wahren, 1968; Owen & Reichard, 1971), 20% to 50% after 72 h of fasting (Owen & Reichard, 1971; Elia et al. 1990), but declines to ∼15% after 24 days of starvation (Owen & Reichard, 1971).”
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    Premisecitation
    § Introduction

    Ketone bodies exert metabolic effects including attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and potential attenuation of proteolysis in skeletal muscle.

    “KBs exert a range of metabolic effects including attenuating glucose utilisation in peripheral tissues, anti‐lipolytic effects on adipose tissue, and potential attenuation of proteolysis in skeletal muscle (Robinson & Williamson, 1980)”
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    Premisecitation
    § Introduction

    The general pattern is for attenuation in trained individuals of the post-exercise rise in [KB], but this is influenced by nutritional manipulation and relative exercise intensity.

    “The general pattern is for attenuation in trained individuals of the post‐exercise rise in [KB], but this is influenced by nutritional manipulation and relative exercise intensity”
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    Premisereasoning
    § Introduction

    Under normal conditions, the contribution of ketone bodies to energy provision in skeletal muscle is less than 5%, and FFAs are the main source of energy provision in the post-absorptive state.

    “because of low circulating concentrations under normal conditions, the contribution to energy provision in muscle is less than 5%, and FFAs are the main source of energy provision in the post‐absorptive state”
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    Premisecitation
    § Introduction

    KB salts are relatively ineffective at increasing [βHB], but may be improved by co-ingestion with medium chain triglycerides (C:8, C:10), at least in rats.

    “These too are relatively ineffective at increasing [βHB], but may be improved by co‐ingestion with medium chain triglycerides (C:8, C:10), at least in rats (Kesl et al. 2016).”
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    Interpretationcitation
    § Introduction

    The regulation of KB oxidation is critical in the starvation response because the capacity of the liver to produce KBs closely matches the requirements of the brain to utilise KBs as an energy source; excessive oxidation by working muscle would threaten survival, whereas its inhibition spares circulating substrate for the brain.

    “This regulation is critical in the starvation response because the capacity of the liver to produce KBs closely matches the requirements of the brain to utilise KBs as an energy source (Robinson & Williamson, 1980). Therefore, excessive oxidation by working muscle would threaten survival, whereas its inhibition spares circulating substrate for the brain (Hagenfeldt & Wahren, 1971; Fery & Balasse,”
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    Premisecitation
    § Introduction

    Ingestion of large quantities of KB salts is impractical due to resulting gastrointestinal distress, and potentially undesirable consequences of cation overload or acidosis.

    “However, ingestion of large quantities of KB salts is impractical due to resulting gastrointestinal distress, and potentially undesirable consequences of cation overload or acidosis (Veech, 2004).”
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    Premisecitation
    § Introduction

    Exercise generally causes a drop in [KB] soon after onset, primarily βHB, concomitant with increases in KB oxidation in skeletal muscle and elevated metabolic clearance rate.

    “This is generally reflected by a drop in [KB] soon after the onset of exercise, primarily βHB, concomitant with increases in KB oxidation in skeletal muscle and elevated metabolic clearance rate (MCR).”
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    Premisecitation
    § Introduction

    When ketosis is achieved by prolonged (>72 h) fasting, there is a negligible contribution of KB oxidation to energy provision; after an overnight fast, the contribution ranges from 2 to 10%.

    “when ketosis is achieved by prolonged (>72 h) fasting there is a negligible contribution of KB oxidation to energy provision (Hagenfeldt & Wahren, 1971; Fery & Balasse, 1986), but after an overnight fast, the contribution ranges from 2 to 10% (Balasse et al. 1978; Fery & Balasse, 1983; Wahren et al. 1984).”
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    Premisecitation
    § Introduction

    There is progressive attenuation of the oxidation of KBs with rising ketonaemia, and thus the mobilisation of KBs is not the factor limiting oxidation in skeletal muscle.

    “Moreover, unlike CHO and fat, there is progressive attenuation of the oxidation of KBs with rising ketonaemia, and thus the mobilisation of KBs is not the factor limiting oxidation in skeletal muscle.”
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    Interpretationcitation
    § Introduction

    The attenuation of exercise-stimulated MCR suggests either that above a threshold concentration the capacity for skeletal muscle to oxidise KBs becomes saturated, and/or that hyperketonaemia itself is a self-inhibitory factor.

    “This attenuation of exercise‐stimulated MCR suggests either that above a threshold concentration the capacity for skeletal muscle to oxidise KBs becomes saturated, and/or that hyperketonaemia itself is a self‐inhibitory factor (Balasse & Fery, 1989).”
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    Premisecitation
    § Introduction

    In Fery & Balasse (1988), AcAc did not change during exercise whereas βHB declined throughout exercise, to be reduced by ∼2 mM at the end of exercise.

    “Notably, AcAc did not change during exercise whereas βHB declined throughout exercise, to be reduced by ∼2 mm at the end of exercise.”
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    Interpretationcitation
    § Introduction

    Mechanistically, the attenuation of exercise-stimulated MCR is likely mediated either through inhibition of OXCT by elevated AcAc, and/or via FFA-mediated inhibition of ketolysis.

    “Mechanistically, this is likely to be mediated either through the inhibition of OXCT by elevated AcAc, and/or via FFA‐mediated inhibition of ketolysis (Robinson & Williamson, 1980).”
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    Premisecitation
    § Introduction

    βHB clearance during a βHB tolerance test is higher in mice given 8 weeks of running wheel access, or with enhanced oxidative capacity consequent to skeletal muscle overexpression of PGC-1α.

    “βHB clearance during a βHB tolerance test is higher in mice given 8 weeks of running wheel access, or with enhanced oxidative capacity consequent to skeletal muscle overexpression of PGC‐1α”
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    • cites Svensson et al. 2016

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    Premisecitation
    § Introduction

    The development of ketone esters provides an alternative method to increase [βHB], which is well-tolerated in rodents and humans.

    “The development of ketone esters provides an alternative method to increase [βHB], which is well‐tolerated in rodents and humans (Clarke et al. 2012; Cox et al. 2016; Kesl et al. 2016).”
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    Premisecitation
    § Introduction

    Elevated MCT1 protein expression after exercise training is well-established for human skeletal muscle, and increases occur in an intensity-dependent manner.

    “Elevated MCT1 protein expression after exercise training is well‐established for human skeletal muscle, and increases occur in an intensity‐dependent manner (Thomas et al. 2012).”
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    Premisecitation
    § Introduction

    KB metabolism during exercise is influenced by metabolic status, training status, and the intensity of exercise.

    “KB metabolism during exercise is influenced by a variety of factors including metabolic status (Wahren et al. 1984; Fery & Balasse, 1986), training status (Johnson & Walton, 1972; Rennie et al. 1974; Beattie & Winder, 1985), and the intensity of exercise (Cox et al. 2016).”
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    Interpretationcitation
    § Introduction

    The majority of work on post-exercise ketosis has compared trained and untrained individuals at the same absolute exercise intensity and duration, which is problematic because relative exercise intensity is the key determinant of the metabolic and hormonal response to acute exercise.

    “the majority of this work has been performed in comparisons, with the absolute exercise intensity and duration being the same for comparisons (reviewed in Koeslag, 1982). This is problematic because the relative exercise intensity is the key determinant of the metabolic and hormonal response to acute exercise”
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    Premisecitation
    § Introduction

    MCR remains above resting values for several hours after exercise, but ketogenesis exceeds ketolysis during this period.

    “MCR remains above resting values for several hours after exercise, but ketogenesis exceeds ketolysis during this period.”
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    Premisecitation
    § Introduction

    An attenuation of, or abolished, post-exercise ketosis has been consistently observed in rodents and humans in response to aerobic exercise in trained versus untrained individuals, or after a period of exercise training.

    “An attenuation of, or abolished, post‐exercise ketosis has been consistently observed in rodents and humans in response to aerobic exercise in trained versus untrained individuals (Johnson et al. 1969; Johnson & Walton, 1972; Rennie et al. 1974), or after a period of exercise training (Rennie & Johnson, 1974a; Beattie & Winder, 1984, 1985; Adams & Koeslag, 1988, 1989; Ohmori et al. 1990).”
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    Premisecitation
    § Introduction

    During post-exercise recovery, muscle glycogen resynthesis has a high metabolic priority and is facilitated by an increase in fat oxidation and sparing of CHO sources for energy provision.

    “During the post‐exercise recovery period, in contrast to the reliance on CHO metabolism during exercise, muscle glycogen resynthesis has a high metabolic priority and is facilitated by an increase in fat oxidation and sparing of CHO sources for energy provision (Kiens & Richter, 1998).”
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    Premisecitation
    § Introduction

    In the post-absorptive state, [KB] rises gradually during prolonged exercise up to 0.2 to 0.4 mM, after which post-exercise ketosis of 0.3 to 2.0 mM is observed for several hours into recovery.

    “In the post‐absorptive state, the pattern generally observed is for [KB] to rise gradually during prolonged exercise up to 0.2 to 0.4 mm, after which time post‐exercise ketosis (PEK) of 0.3 to 2.0 mm is observed for several hours into recovery (Koeslag, 1982).”
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    Interpretationreasoning
    § Introduction

    When liver glycogen becomes depleted and glucagon:insulin ratio is elevated, the synthesis of malonyl CoA is reduced, thereby relieving the inhibition of fat transport into hepatocytes, and resulting in elevated levels of Ac-CoA.

    “When liver glycogen becomes depleted and glucagon:insulin ratio is elevated, the synthesis of malonyl CoA is reduced, thereby relieving the inhibition of fat transport into hepatocytes, and resulting in elevated levels of Ac‐CoA.”
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    Interpretationreasoning
    § Introduction

    Reductions in glycolytic flux with low glycogen content after intense exercise result in oxaloacetate moving to cytoplasm for preferential use in gluconeogenesis, which allows diversion of Ac-CoA towards ketogenesis during the post-exercise period rather than to citrate synthesis for the TCA cycle.

    “reductions in glycolytic flux with low glycogen content after intense exercise result in oxaloacetate moving to cytoplasm for preferential use in gluconeogenesis, which allows diversion of Ac‐CoA towards ketogenesis during the post‐exercise period rather than to citrate synthesis for the TCA cycle.”
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    Premisecitation
    § Introduction

    Subsequent experiments with ingestion of the KE demonstrated inhibition of glycolytic metabolism, sparing of muscle glycogen, reduced deamination of branched-chain amino acids, and increased reliance on IMTG during exercise.

    “Subsequent experiments with ingestion of the KE demonstrated inhibition of glycolytic metabolism, sparing of muscle glycogen, reduced deamination of branched‐chain amino acids, and increased reliance on IMTG during exercise (Cox et al. 2016).”
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    Interpretationreasoning
    § Introduction

    The enhanced ketolytic capacity and downregulation of ketogenic capacity by training may play a role in the attenuation of post-exercise ketosis.

    “The aforementioned enhanced ketolytic capacity and downregulation of ketogenic capacity by training may play a role in these observations”
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    Interpretationown data
    § Introduction

    Acute nutritional ketosis by consumption of exogenous ketones has dramatic effects on skeletal muscle metabolism during exercise, and can confer a performance benefit to elite athletes.

    “Taken together, these data suggest that acute nutritional ketosis by consumption of exogenous ketones has dramatic effects on skeletal muscle metabolism during exercise, and can confer a performance benefit to elite athletes (Fig. 3).”
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    Premisecitation
    § Introduction

    The KE + CHO fuelling strategy combined KE (40%; 573 mg (kg BM)−1) with CHO (60%) and elevated [βHB] to between ∼1.5 and 3 mM throughout.

    “The KE + CHO fuelling strategy combined KE (40%; 573 mg (kg BM)−1) with CHO (60%) and elevated [βHB] to between ∼1.5 and 3 mm throughout.”
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    Premisecitation
    § Introduction

    KBs have protein sparing effects in skeletal muscle as indicated by reduced alanine release during starvation and reduced leucine oxidation.

    “KBs have protein sparing effects in skeletal muscle as indicated by reduced alanine release during starvation (Sherwin et al. 1975), and reduced leucine oxidation (Nair et al. 1988).”
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    Premisecitation
    § Introduction

    Inhibition of lipolysis via nicotinic acid impaired cycling time-trial performance in long (120 min), but not shorter (60 and 90 min) duration efforts.

    “Recently, the inhibition of lipolysis via nicotinic acid impaired cycling time‐trial performance in long (120 min), but not shorter (60 and 90 min) duration efforts (Torrens et al. 2016).”
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    Interpretationreasoning
    § Introduction

    The central nervous system (CNS) may be another target for performance-enhancing effects of nutritional ketosis.

    “Because KBs serve as a substrate for the brain, and therapeutic uses for KBs have been proposed for cognitive enhancement and neurodegenerative pathologies (Veech, 2004), the central nervous system (CNS) may be another target for performance‐enhancing effects of nutritional ketosis.”
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    Premisenone given
    § Introduction

    The inhibitory effects of βHB on HDAC were observed in multiple tissues but remain to be confirmed in skeletal muscle.

    “However, although the inhibitory effects were observed in multiple tissues, they remain to be confirmed in skeletal muscle.”
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    Interpretationnone given
    § Introduction

    The mechanistic basis for CHO sparing by exogenous ketones is presently proposed as inhibition of glycolytic flux via inhibition of PDH and PFK by increases in NADH:NAD+, acetyl-CoA:CoA ratio or citrate.

    “The mechanistic basis for CHO sparing by exogenous ketones is presently proposed as inhibition of glycolytic flux via inhibition of PDH and PFK by increases in NADH:NAD+, acetyl‐CoA:CoA ratio or citrate.”
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    Premisecitation
    § Introduction

    Mice supplemented with sodium butyrate are resistant to diet-induced obesity, and have elevations in markers of skeletal muscle mitochondrial biogenesis analogous to exercise effects.

    “Mice supplemented with sodium butyrate are resistant to diet‐induced obesity, and have elevations in markers of skeletal muscle mitochondrial biogenesis analogous to exercise effects (Gao et al. 2009).”
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    Interpretationreasoning
    § Introduction

    If the same effect occurs in skeletal muscle, this would translate as a higher power output for the same oxygen consumption (i.e. improved muscular efficiency) during exercise with nutritional ketosis.

    “In practical terms, if the same effect occurs in skeletal muscle, this would translate as a higher power output for the same oxygen consumption (i.e. improved muscular efficiency) during exercise with nutritional ketosis, but this remains unexplored at present.”
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    Premisecitation
    § Introduction

    Class IIa HDAC function is responsive to both aerobic endurance exercise in humans and nutritional intervention in rodents.

    “their function is responsive to both aerobic endurance exercise in humans (McGee et al. 2009; Egan et al. 2010) and nutritional intervention in rodents (Gao et al. 2009; Shimazu et al. 2013).”
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    Premisecitation
    § Introduction

    A preliminary report describes a 33% increase in glucose disposal and 50% increase in muscle glycogen content after 2 h of recovery when nutritional ketosis (∼5 mm βHB) is superimposed on a hyperglycaemic (10 mm glucose) clamp in well-trained military servicemen.

    “a preliminary report describes a 33% increase in glucose disposal and 50% increase in muscle glycogen content after 2 h of recovery when nutritional ketosis (∼5 mm βHB) is superimposed on a hyperglycaemic (10 mm glucose) clamp in well‐trained military servicemen (Holdsworth et al. 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Holdsworth et al. 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction

    Alterations in fuel selection during steady-state exercise have been demonstrated, which indicate reduced glycolytic flux, sparing of CHO and increased contribution of IMTG and βHB to energy provision.

    “Alterations in fuel selection during steady‐state exercise have been demonstrated, which indicate reduced glycolytic flux, sparing of CHO and increased contribution of IMTG and βHB to energy provision (Cox et al. 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cox et al. 2016

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § Introduction

    Given the saturation kinetics of KB oxidation by skeletal muscle and curvilinear relationship between oxidation and plasma concentrations, it is likely that there is an optimal range for performance benefits.

    “Given the saturation kinetics of KB oxidation by skeletal muscle and curvilinear relationship between oxidation and plasma concentrations, it is likely that there is an optimal range for performance benefits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § Introduction

    Exogenous ketone supplementation may provide both a fuel source and contribute to protein sparing and recovery during training in CHO-restricted states commonly practiced by athletes.

    “exogenous ketone supplementation may provide both a fuel source and contribute to protein sparing and recovery during training in CHO‐restricted states commonly practiced by athletes (reviewed in Bartlett et al. 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bartlett et al. 2015

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Introduction

    Acute nutritional ketosis achieved by exogenous ketone supplementation has the potential to alter fuel selection during exercise and confer performance benefits.

    “In conclusion, although data are preliminary, acute nutritional ketosis achieved by exogenous ketone supplementation has the potential to alter fuel selection during exercise and confer performance benefits.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Introduction

    Improved energetic efficiency is an often-cited potential benefit of acute nutritional ketosis.

    “Improved energetic efficiency is an often‐cited potential benefit of acute nutritional ketosis (Veech, 2004; Cox & Clarke, 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Veech, 2004

      Not checked in the free run.

    • cites Cox & Clarke, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction

    Support for this hypothesis comes from a perfused working rat heart model where adding KBs to the perfusate suppressed glycolytic flux, and increased hydraulic efficiency (expressed as work in J (mol O2 consumed)−1) by 28%.

    “Support for this hypothesis comes from a perfused working rat heart model where adding KBs to the perfusate supressed glycolytic flux, and increased hydraulic efficiency (expressed as work in J (mol O2 consumed)−1) by 28% (Sato et al. 1995; Kashiwaya et al. 1997).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Sato et al. 1995

      Not checked in the free run.

    • cites Kashiwaya et al. 1997

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction

    An acute bout of aerobic exercise increases class IIa HDAC phosphorylation and subsequent nuclear exclusion, thus inhibiting HDAC-mediated repression of specific exercise-responsive genes such as GLUT4 and PGC-1α.

    “An acute bout of aerobic exercise increases class IIa HDAC phosphorylation and subsequent nuclear exclusion, thus inhibiting HDAC‐mediated repression of specific exercise‐responsive genes such as GLUT4 and PGC‐1α (McGee & Hargreaves, 2004; McGee et al. 2009; Egan et al. 2010).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites McGee & Hargreaves, 2004

      Not checked in the free run.

    • cites McGee et al. 2009

      Not checked in the free run.

    • cites Egan et al. 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction

    In the KE experiments, glycogenolysis was attenuated and IMTG utilisation was increased.

    “In fact, glycogenolysis was attenuated and IMTG utilisation was increased in the KE experiments (Cox et al. 2016), suggesting differential regulation to that achieved by nicotinic acid administration (van Loon et al. 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cox et al. 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction

    βHB, although not as potent as butyrate, also inhibits HDAC class I and II activity in a dose-dependent manner and suppressed oxidative stress responses.

    “βHB is structurally similar to butyrate, and although not as potent as butyrate, also inhibits HDAC class I and II activity in a dose‐dependent manner and supressed oxidative stress responses (Shimazu et al. 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shimazu et al. 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § Introduction

    This potential is most likely to be the case in trained individuals who have a greater capacity to take up and oxidise KBs during exercise as a result of training.

    “This is most likely to be the case in trained individuals who have a greater capacity to take up and oxidise KBs during exercise as a result of training.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Introduction

    In the Nair et al. study, reduced leucine oxidation coincided with a 10% increase in muscle protein synthesis (MPS) measured by fractional synthesis rate and occurred with [βHB] of ∼2 mm achieved via sodium βHB infusion.

    “In the latter study, this coincided with a 10% increase in MPS measured by fractional synthesis rate and occurred with [βHB] of ∼2 mm achieved via sodium βHB infusion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nair et al. 1988

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation
    § Introduction

    In this model, exogenous ketones may provide thermodynamic advantages over CHO and fat, because the available free energy to perform work, the free energy of ATP hydrolysis (ΔG′ATP), is greater with KBs, and require less oxygen per mole of carbon to oxidise.

    “In this model, exogenous ketones may provide thermodynamic advantages over CHO and fat, because the available free energy to perform work, the free energy of ATP hydrolysis (ΔG′ATP), is greater with KBs, and require less oxygen per mole of carbon to oxidise.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Veech, 2004

      Not checked in the free run.

    • cites Cox & Clarke, 2014

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given
    § Introduction

    A strong physiological basis exists that suggests potential benefits for supporting training and recovery.

    “Additionally, a strong physiological basis exists that suggests potential benefits for supporting training and recovery.”
    Quote in the paperNot a substantial claim
53 of 53

  • The paper relies on this without support.

    Training-induced changes in expression and activities of enzymes of ketolysis in human skeletal muscle have not been described.

    “Training‐induced changes in expression and activities of enzymes of ketolysis in skeletal muscle have not been described in humans”

  • The paper relies on this without support.

    Oral administration of ketone bodies in their free acid form is expensive and ineffective at producing ketosis.

    “Oral administration of KBs in their free acid form is expensive and ineffective at producing ketosis”

  • The paper relies on this without support.

    The brain cannot utilise free fatty acids as a fuel source.

    “providing a substrate for brain, which cannot utilise FFAs as a fuel source”

  • The paper relies on this without support.

    Alanine ingestion increases mitochondrial [oxaloacetate] in liver, thereby allowing condensation with Ac-CoA and diversion away from ketogenesis.

    “Alanine ingestion increases mitochondrial [oxaloacetate] in liver, thereby allowing condensation with Ac‐CoA and diversion away from ketogenesis.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In some populations, enhancements in training status might lead to an increase in muscle oxidation of ketone bodies leading to a greater underestimation of their contribution in the post-intervention phase.

    “we acknowledge that in some populations, enhancements in training status might lead to an increase in muscle oxidation of ketone bodies leading to a greater underestimation of their contribution in the post-intervention phase [56].”

    From Crisis of confidence averted: impairment of exercise economy and performance in elite race walkers by ketogenic low carbohydrate, high fat (LCHF) diet is reproducible (2020) · cites this paper as [56]

  • High circulating concentrations of ketone bodies could inhibit the flux of other muscle substrates, either by impairing muscle carbohydrate oxidation and/or inhibiting adipose tissue lipolysis.

    “Nevertheless, there is some concern that the presence of high circulating concentrations of ketone bodies could inhibit the flux of other muscle substrates, either by impairing (rather than “sparing”) muscle CHO oxidation and/or inhibiting adipose tissue lipolysis (Evans et al., 2017).”

    From Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists (2017) · cites this paper as Evans et al., 2017

  • A ketone monoester, R-3-hydroxybutyl R-3-hydroxybutyrate, increases plasma ketone concentrations (3-6 mmol/L) within the hours following its ingestion (400-600 mg/kg BM), although this may be altered by concomitant intake of food.

    “Recently, a newly produced ketone monoester, R-3-hydroxybutyl R-3-hydroxybutyrate (Clarke et al., 2012), increases in plasma ketone concentrations (3–6 mmol/L) within the hours following its ingestion (400–600 mg/kg BM), although this may be altered by concomitant intake of food (Evans et al., 2017; Pinckaers et al., 2017).”

    From Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists (2017) · cites this paper as Evans et al., 2017

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Abraham R, 2015, Ketones: Controversial new energy drink could be next big thing in cycling, Cycling Weekly

Cited by

Sorted by citations

Related

Authors
Evans, M., Cogan, K. E., & Egan, B.
Affiliations
University College Dublin (IE)
Corresponding author
Egan, Brendan
ORCID
Egan, Brendan
Venue
The Journal of Physiology
Publisher
Wiley
Published
2016-12-07
Volume
595
Issue
9
Pages
2857-2871
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1113/jp273185
PMC
PMC5407977
OpenAlex
W2556344533
Cited by
414
References
85
Citations by year
2026: 33 · 2025: 60 · 2024: 40 · 2023: 57 · 2022: 51 · 2021: 60 · 2020: 54 · 2019: 34 · 2018: 18 · 2017: 7
FWCI
2.31
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
University College Dublin
Topics
  • Health Sciences › Medicine › Physiology › Diet and metabolism studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Sports Performance and Training
Keywords
ketone bodies, beta-hydroxybutyrate, acetoacetate, acetone, ketone esters, exogenous ketone supplementation, physical activity, training, skeletal muscle, fuel selection, glucose utilization, lipolysis, proteolysis, histone deacetylase inhibition, post-exercise recovery, exercise performance
MeSH terms
Humans, Ketone Bodies, Ketosis, Exercise, Dietary Supplements

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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