Defining ketone supplementation: the evolving evidence for postexercise ketone supplementation to improve recovery and adaptation to exercise.

Over the last decade, there has been a growing interest in the use of ketone supplements to improve athletic performance. These ketone supplements transiently elevate the concentrations of the ketone bodies acetoacetate (AcAc) and d-ß-hydroxybutyrate (ßHB) in the circulation. Early studies showed that ketone bodies can improve energetic efficiency in striated muscle compared with glucose oxidation and induce a glycogen-sparing effect during exercise. As such, most research has focused on the potential of ketone supplementation to improve athletic performance via ingestion of ketones immediately before or during exercise. However, subsequent studies generally observed no performance improvement, and particularly not under conditions that are relevant for most athletes. However, more and more studies are reporting beneficial effects when ketones are ingested after exercise. As such, the real potential of ketone supplementation may rather be in their ability to enhance postexercise recovery and training adaptations. For instance, recent studies observed that postexercise ketone supplementation (PEKS) blunts the development of overtraining symptoms, and improves sleep, muscle anabolic signaling, circulating erythropoietin levels, and skeletal muscle angiogenesis. In this review, we provide an overview of the current state-of-the-art about the impact of PEKS on aspects of exercise recovery and training adaptation, which is not only relevant for athletes but also in multiple clinical conditions. In addition, we highlight the underlying mechanisms by which PEKS may improve exercise recovery and training adaptation. This includes epigenetic effects, signaling via receptors, modulation of neurotransmitters, energy metabolism, and oxidative and anti-inflammatory pathways.

Partly Substituting Whey for Collagen Peptide Supplementation Improves Neither Indices of Muscle Damage Nor Recovery of Functional Capacity During Eccentric Exercise Training in Fit Males.

Previous studies showed that collagen peptide supplementation along with resistance exercise enhance muscular recovery and function. Yet, the efficacy of collagen peptide supplementation in addition to standard nutritional practices in athletes remains unclear. Therefore, the objective of the study was to compare the effects of combined collagen peptide (20 g) and whey protein (25 g) supplementation with a similar daily protein dose (45 g) of whey protein alone on indices of muscle damage and recovery of muscular performance during eccentric exercise training. Young fit males participated in a 3-week training period involving unilateral eccentric exercises for the knee extensors. According to a double-blind, randomized, parallel-group design, before and after training, they received either whey protein (n = 11) or whey protein + collagen peptides (n = 11). Forty-eight hours after the first training session, maximal voluntary isometric and dynamic contraction of the knee extensors were transiently impaired by ∼10% (Ptime < .001) in whey protein and whey protein + collagen peptides, while creatine kinase levels were doubled in both groups (Ptime < .01). Furthermore, the training intervention improved countermovement jump performance and maximal voluntary dynamic contraction by respectively 8% and 10% (Ptime < .01) and increased serum procollagen type 1N-terminal peptide concentration by 10% (Ptime < .01). However, no differences were found for any of the outcomes between whey and whey protein + collagen peptides. In conclusion, substituting a portion of whey protein for collagen peptide, within a similar total protein dose, improved neither indices of eccentric muscle damage nor functional outcomes during eccentric training.

Exogenous Ketosis Improves Sleep Efficiency and Counteracts the Decline in REM Sleep after Strenuous Exercise.

INTRODUCTION: Available evidence indicates that ketone bodies may improve sleep quality. Therefore, we determined whether ketone ester (KE) intake could counteract sleep disruptions induced by strenuous exercise. METHODS: Ten well-trained cyclists with good sleep quality participated in a randomized crossover design consisting of two experimental sessions each involving a morning endurance training and an evening high-intensity interval training ending 1 h before sleep, after which polysomnography was performed overnight. Postexercise and 30 min before sleeping time, subjects received either 25 g of KE (EX KE ) or a placebo drink (EX CON ). A third session without exercise but with placebo supplements (R CON ) was added to evaluate the effect of exercise per se on sleep. RESULTS: Blood d -ß-hydroxybutyrate concentrations transiently increased to ~3 mM postexercise and during the first part of the night in EX KE but not in EX CON or R CON . Exercise significantly reduced rapid eye movement sleep by 26% ( P = 0.001 vs R CON ) and increased wakefulness after sleep onset by 95% ( P = 0.004 vs R CON ). Interestingly, KE improved sleep efficiency by 3% ( P = 0.040 vs EX CON ) and counteracted the exercise-induced decrease in rapid eye movement sleep ( P = 0.011 vs EX CON ) and the increase in wakefulness after sleep onset ( P = 0.009 vs EX CON ). This was accompanied by a KE-induced increase in dopamine excretion ( P = 0.033 vs EX CON ), which plays a pivotal role in sleep regulation. In addition, exercise increased sleep spindle density by 36% ( P = 0.005 vs R CON ), suggesting an effect on neural plasticity processes during sleep. CONCLUSIONS: These data indicate that KE ingestion improves sleep efficiency and quality after high-intensity exercise. We provide preliminary evidence that this might result from KE-induced increases in dopamine signaling.

Exogenous ketosis increases circulating dopamine concentration and maintains mental alertness in ultra-endurance exercise.

Exogenous ketosis can improve psychocognitive functioning during exercise as well as stimulate postexercise muscular recovery. Therefore, we hypothesized that ketone ester (KE) supplementation can counteract the decline in psychocognitive functioning during ultra-endurance exercise and stimulate muscular recovery. Eighteen recreational runners participated in a full 100 km trail run (RUN, n = 8), or ran to premature exhaustion (80 km: n = 6; 60 km: n = 4). Before (25 g), during (25 g·h-1), and after (5 × 25 g in 24 h) RUN they received ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE, n = 9) supplements or a noncaloric placebo (CON, n = 9). Blood samples and muscle biopsies were taken, and mental alertness was assessed by a psychocognitive test battery at different times before, during, and up to 36 h after RUN. Compared with CON (<0.3 mM), in KE blood d-ß-hydroxybutyrate concentration was consistently elevated to ∼2-3 mM during RUN. In CON, RUN increased visual reaction times from 353 ± 53 to 419 ± 54 ms, and movement execution times from 174 ± 47 to 245 ± 64 ms. But this effect was fully negated by KE (P < 0.05). Plasma dopamine concentrations doubled in KE during RUN but remained stable in CON, resulting in higher concentrations after RUN in KE (4.1 ± 1.7 nM) than in CON (2.4 ± 0.8 nM, P = 0.048). KE also inhibited muscular infiltration of macrophages and suppressed AMPK phosphorylation status until 36-h postexercise (P < 0.05 KE vs. CON). In conclusion, KE increases circulating dopamine concentration and improves mental alertness, as well as improves postexercise muscular inflammation in ultra-endurance exercise.NEW & NOTEWORTHY Oral ketone ester ingestion elevates circulating dopamine concentration during ultra-endurance exercise. This is associated with improved mental alertness. Furthermore, ketone ester intake inhibits postexercise skeletal muscle macrophage infiltration, and counteracts the increase in AMPK phosphorylation after exercise, which indicates improved muscular energy status.

Exogenous ketosis elevates circulating erythropoietin and stimulates muscular angiogenesis during endurance training overload.

De novo capillarization is a primary muscular adaptation to endurance exercise training and is crucial to improving performance. Excess training load, however, impedes such beneficial adaptations, yet we recently demonstrated that such downregulation may be counteracted by ketone ester ingestion (KE) post-exercise. Therefore, we investigated whether KE could increase pro-angiogenic factors and thereby stimulate muscular angiogenesis during a 3-week endurance training-overload period involving 10 training sessions/week in healthy, male volunteers. Subjects received either 25 g of a ketone ester (KE, n = 9) or a control drink (CON, n = 9) immediately after each training session and before sleep. In KE, but not in CON, the training intervention increased the number of capillary contacts and the capillary-to-fibre perimeter exchange index by 44% and 42%, respectively. Furthermore, KE also substantially increased vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression both at the protein and at the mRNA level. Serum erythropoietin concentration was concomitantly increased by 26%. Conversely, in CON the training intervention increased only the protein content of eNOS. These data indicate that intermittent exogenous ketosis during endurance overload training stimulates muscular angiogenesis. This likely resulted from a direct stimulation of muscle angiogenesis, which may be at least partly due to stimulation of erythropoietin secretion and elevated VEGF activity, and/or an inhibition of the suppressive effect of overload training on the normal angiogenic response to training. This study provides novel evidence to support the potential of exogenous ketosis to benefit endurance training-induced muscular adaptation. KEY POINTS: Increased capillarization is a primary muscular adaptation to endurance exercise training. However, excess training load may impede such response. We previously observed that intermittent exogenous ketosis by post-exercise and pre-sleep ketone ester ingestion (KE) counteracted physiological dysregulations induced by endurance overload training. Therefore, we investigated whether KE could increase pro-angiogenic factors thereby stimulating muscular angiogenesis during a 3-week endurance training overload period. We show that the overload training period in the presence, but not in the absence, of KE markedly increased muscle capillarization (+40%). This increase was accompanied by higher circulating erythropoietin concentration and stimulation of the pro-angiogenic factors vascular endothelial growth factor and endothelial nitric oxide synthase in skeletal muscle. Collectively, our data indicate that intermittent exogenous ketosis may evolve as a potent nutritional strategy to facilitate recovery from strenuous endurance exercise, thereby stimulating beneficial muscular adaptations.

Exogenous ketosis suppresses diuresis and atrial natriuretic peptide during exercise.

We have previously demonstrated that exogenous ketosis reduces urine production during exercise. However, the underlying physiological mechanism of this antidiuretic effect remained unclear. Therefore, we investigated whether acute exogenous ketosis by oral ingestion of ketone ester (KE) during a simulated cycling race (RACE) affects the hormonal pathways implicated in fluid balance regulation during exercise. In a double-blind crossover design, 11 well-trained male cyclists participated in RACE consisting of a 3-h submaximal intermittent cycling (IMT180') bout followed by a 15-min time trial (TT15') in an environmental chamber set at 28°C and 60% relative humidity. Fluid intake was adjusted to maintain euhydration. Before and during RACE, the subjects received either a control drink (CON) or the ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE), which elevated blood ß-hydroxybutyrate to ∼2-4 mM. Urine output during IMT180' was ∼20% lower in KE (1,172 ± 557 mL) than in CON (1,431 ± 548 mL, P < 0.05). Compared with CON, N-terminal proatrial natriuretic peptide (NT-pro ANP) concentration during RACE was ∼20% lower in KE (P < 0.05). KE also raised plasma noradrenaline concentrations during RACE. Performance in TT15' was similar between CON and KE. In conclusion, exogenous ketosis suppresses diuresis and downregulates NT-pro ANP secretion during exercise.NEW & NOTEWORTHY We previously demonstrated that exogenous ketosis reduces urine production during exercise, however, the underlying physiological mechanism remained unclear. Here, we, for the first time demonstrate that exogenous ketosis suppresses the exercise-induced release of atrial natriuretic peptide (ANP). However, given the limited effects of ANP on renal haemodynamics during exercise, the underlying physiological mechanism remains unknown. But downregulation of ANP might explain a new physiological mechanism by which exogenous ketosis lowers blood-free fatty acid levels.

Exogenous ketosis increases blood and muscle oxygenation but not performance during exercise in hypoxia.

Available evidence indicates that elevated blood ketones are associated with improved hypoxic tolerance in rodents. From this perspective, we hypothesized that exogenous ketosis by oral intake of the ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE) may induce beneficial physiological effects during prolonged exercise in acute hypoxia. As we recently demonstrated KE to deplete blood bicarbonate, which per se may alter the physiological response to hypoxia, we evaluated the effect of KE both in the presence and absence of bicarbonate intake (BIC). Fourteen highly trained male cyclists performed a simulated cycling race (RACE) consisting of 3-h intermittent cycling (IMT180') followed by a 15-min time-trial (TT15') and an all-out sprint at 175% of lactate threshold (SPRINT). During RACE, fraction of inspired oxygen ([Formula: see text]) was gradually decreased from 18.6% to 14.5%. Before and during RACE, participants received either 1) 75 g of ketone ester (KE), 2) 300 mg/kg body mass bicarbonate (BIC), 3) KE + BIC, or 4) a control drink in addition to 60 g of carbohydrates/h in a randomized, crossover design. KE counteracted the hypoxia-induced drop in blood ([Formula: see text]) and muscle oxygenation by ∼3%. In contrast, BIC decreased [Formula: see text] by ∼2% without impacting muscle oxygenation. Performance during TT15' and SPRINT were similar between all conditions. In conclusion, KE slightly elevated the degree of blood and muscle oxygenation during prolonged exercise in moderate hypoxia without impacting exercise performance. Our data warrant to further investigate the potential of exogenous ketosis to improve muscular and cerebral oxygenation status, and exercise tolerance in extreme hypoxia.