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Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models.

ABSTRACT: Nutritional ketosis has been proven effective for neurometabolic conditions and disorders linked to metabolic dysregulation. While inducing nutritional ketosis, ketogenic diet (KD) can improve motor performance in the context of certain disease states, but it is unknown whether exogenous ketone supplements-alternatives to KDs-may have similar effects. Therefore, we investigated the effect of ketone supplements on motor performance, using accelerating rotarod test and on postexercise blood glucose and R-beta-hydroxybutyrate (R-?HB) levels in rodent models with and without pathology. The effect of KD, butanediol (BD), ketone-ester (KE), ketone-salt (KS), and their combination (KE + KS: KEKS) or mixtures with medium chain triglyceride (MCT) (KE + MCT: KEMCT; KS + MCT: KSMCT) was tested in Sprague-Dawley (SPD) and WAG/Rij (WR) rats and in GLUT-1 Deficiency Syndrome (G1D) mice. Motor performance was enhanced by KEMCT acutely, KE and KS subchronically in SPD rats, by KEKS and KEMCT groups in WR rats, and by KE chronically in G1D mice. We demonstrated that exogenous ketone supplementation improved motor performance to various degrees in rodent models, while effectively elevated R-?HB and in some cases offsets postexercise blood glucose elevations. Our results suggest that improvement of motor performance varies depending on the strain of rodents, specific ketone formulation, age, and exposure frequency.

SUBMITTER: Ari C

PROVIDER: S-EPMC7468837 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models.

Ari Csilla C Murdun Cem C Goldhagen Craig C Koutnik Andrew P AP Bharwani Sahil R SR Diamond David M DM Kindy Mark M D'Agostino Dominic P DP Kovacs Zsolt Z

Nutrients 20200815 8

Nutritional ketosis has been proven effective for neurometabolic conditions and disorders linked to metabolic dysregulation. While inducing nutritional ketosis, ketogenic diet (KD) can improve motor performance in the context of certain disease states, but it is unknown whether exogenous ketone supplements-alternatives to KDs-may have similar effects. Therefore, we investigated the effect of ketone supplements on motor performance, using accelerating rotarod test and on postexercise blood glucos ...[more]

PMID: 32824223

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Project description:BackgroundInterest into the health, disease, and performance impact of exogenous ketone bodies has rapidly expanded due to their multifaceted physiological and signaling properties but limiting our understanding is the isolated analyses of individual types and dose/dosing protocols.MethodsThirteen recreational male distance runners (24.8 ± 9.6 years, 72.5 ± 8.3 kg, VO2max 60.1 ± 5.4 ml/kg/min) participated in this randomized, double-blind, crossover design study. The first two sessions consisted of a 5-km running time trial familiarization and a VO2max test. During subsequent trials, subjects were randomly assigned to one (KS1: 22.1 g) or two (KS2: 44.2 g) doses of beta-hydroxybutyrate (βHB) and medium chain triglycerides (MCTs) or flavor matched placebo (PLA). Blood R-βHB, glucose, and lactate concentrations were measured at baseline (0-min), post-supplement (30 and 60 min), post-exercise (+ 0 min, + 15 min). Time, heart rate (HR), rating of perceived exertion (RPE), affect, respiratory exchange ratio, oxygen consumption (VO2), carbon dioxide production, and ventilation were measured during exercise. Cognitive performance was evaluated prior to and post-exercise.ResultsKS significantly increased R-βHB, with more potent and prolonged elevations in KS2, illustrating an administrative and dosing effect. R-βHB was significantly decreased in KS1 compared to KS2 illustrating a dosing and exercise interaction effect. Blood glucose elevated post-exercise but was unchanged across groups. Blood lactate significantly increased post-exercise but was augmented by KS administration. Gaseous exchange, respiration, HR, affect, RPE, and exercise performance was unaltered with KS administration. However, clear responders and none-responders were indicated. KS2 significantly augmented cognitive function in pre-exercise conditions, while exercise increased cognitive performance for KS1 and PLA to pre-exercise KS2 levels.ConclusionNovel βHB + MCT formulation had a dosing effect on R-βHB and cognitive performance, an administrative response on blood lactate, while not influencing gaseous exchange, respiration, HR, affect, RPE, and exercise performance.

Project description:BackgroundAccumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models.MethodsTwo independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available β-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet.ResultsThe KE-1 diet in mice elevated β-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P=0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P<0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2-treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values.ConclusionsChronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.

Project description:Exogenous ketone ester and ketone ester mixed with ketone free acid formulations are rapidly entering the commercial marketspace. Short-term animal and human studies using these products suggest significant potential for primary or secondary prevention of a number of chronic disease conditions. However, a number of questions need to be addressed by the field for optimal use in humans, including variable responses among available exogenous ketones at different dosages; frequency of dosing; and their tolerability, acceptability, and efficacy in long-term clinical trials. The purpose of the current investigation was to examine the tolerability, acceptability, and circulating R-beta-hydroxybutyrate (R-βHB) and glucose responses to a ketone monoester (KME) and ketone monoester/salt (KMES) combination at 5 g and 10 g total R-βHB compared with placebo control (PC). Fourteen healthy young adults (age: 21 ± 2 years, weight: 69.7 ± 14.2 kg, percent fat: 28.1 ± 9.3%) completed each of the five study conditions: placebo control (PC), 5 g KME (KME5), 10 g KME (KME10), 5 g (KMES5), and 10 g KMES (KMES10) in a randomized crossover fashion. Circulating concentrations of R-βHB were measured at baseline (time 0) following an 8-12 h overnight fast and again at 15, 30, 60, and 120 min following drink ingestion. Participants also reported acceptability and tolerability during each condition. Concentrations of R-βHB rose to 2.4 ± 0.1 mM for KME10 after 15 min, whereas KMES10 similarly peaked (2.1 ± 0.1 mM) but at 30 min. KME5 and KMES5 achieved similar peak R-βHB concentrations (1.2 ± 0.7 vs. 1.1 ± 0.5 mM) at 15 min. Circulating R-βHB concentrations were similar to baseline for each condition by 120 min. Negative correlations were observed between R-βHB and glucose at the 30 min time point for each condition except KME10 and PC. Tolerability was similar among KME and KMES, although decreases in appetite were more frequently reported for KMES. Acceptability was slightly higher for KMES due to the more frequently reported aftertaste for KME. The results of this pilot investigation illustrate that the KME and KMES products used increase circulating R-βHB concentrations to a similar extent and time course in a dose-dependent fashion with slight differences in tolerability and acceptability. Future studies are needed to examine variable doses, frequency, and timing of exogenous ketone administration for individuals seeking to consume ketone products for health- or sport performance-related purposes.

Project description:BackgroundInterest in therapeutic applications of exogenous ketones has grown significantly, spanning patients with heart failure to endurance athletes. Exogenous ketones engender significant effects on cardiac function in heart failure and provide an ergogenic benefit in athletes. The aim of this study was to assess the effects of exogenous ketones on cardiac function in healthy participants.MethodsIn a single-arm intervention study, 20 fasting, healthy participants underwent comprehensive echocardiography (two-dimensional, Doppler, and strain) before and 30 min after weight-based oral ketone ester administration. The relationship between changes in log-transformed biomarker levels and change in absolute global longitudinal strain (GLS) was assessed using linear regression.ResultsThe mean age was 30 ± 7 years, 50% were women, 45% were nonwhite, and the average body mass index was 24.3 ± 3.1 kg/m2. Ketone ingestion acutely elevated β-hydroxybutyrate levels from a median of 0.13 mmol/L (interquartile range, 0.10-0.37 mmol/L) to 3.23 mmol/L (interquartile range, 2.40-4.97 mmol/L) (P < .001). After ketone ester consumption, systolic blood pressure, heart rate, biventricular function, left ventricular GLS, and left atrial (LA) strain all augmented, while systemic vascular resistance decreased. Displayed as mean change, increases in ejection fraction (3.1%; 95% CI, 2.0%-4.2%; P < .001), GLS (2.0%; 95% CI, 1.4%-2.7%; P < .001), right ventricular S' (1.1 cm/sec; 95% CI, 0.4-1.8 cm/sec; P = .004), LA reservoir strain (7%; 95% CI, 3%-12%; P = .005), and LA contractile strain (4%; 2%-6%; P = .001) were observed. During robustly achieved ketosis, change in GLS was inversely associated with change in nonesterified fatty acids (P = .019).ConclusionsIn a single-arm study, systolic blood pressure, heart rate, biventricular function, and LV and LA strain acutely augmented after ketone ester ingestion in healthy, fasting participants, similar to several effects observed in the failing heart. These data may provide supporting data for the ergogenic benefits observed in athletes and may become increasingly relevant with exogenous ketone consumption across a variety of cardiovascular and noncardiovascular applications.

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Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models.

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Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models.

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