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      Ketone ester supplementation blunts overreaching symptoms during endurance training overload

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          Abstract

          Key points

          • Overload training is required for sustained performance gain in athletes (functional overreaching). However, excess overload may result in a catabolic state which causes performance decrements for weeks (non‐functional overreaching) up to months (overtraining).

          • Blood ketone bodies can attenuate training‐ or fasting‐induced catabolic events. Therefore, we investigated whether increasing blood ketone levels by oral ketone ester (KE) intake can protect against endurance training‐induced overreaching.

          • We show for the first time that KE intake following exercise markedly blunts the development of physiological symptoms indicating overreaching, and at the same time significantly enhances endurance exercise performance.

          • We provide preliminary data to indicate that growth differentiation factor 15 (GDF15) may be a relevant hormonal marker to diagnose the development of overtraining.

          • Collectively, our data indicate that ketone ester intake is a potent nutritional strategy to prevent the development of non‐functional overreaching and to stimulate endurance exercise performance.

          Abstract

          It is well known that elevated blood ketones attenuate net muscle protein breakdown, as well as negate catabolic events, during energy deficit. Therefore, we hypothesized that oral ketones can blunt endurance training‐induced overreaching. Fit male subjects participated in two daily training sessions (3 weeks, 6 days/week) while receiving either a ketone ester (KE, n = 9) or a control drink (CON, n = 9) following each session. Sustainable training load in week 3 as well as power output in the final 30 min of a 2‐h standardized endurance session were 15% higher in KE than in CON (both P < 0.05). KE inhibited the training‐induced increase in nocturnal adrenaline ( P < 0.01) and noradrenaline ( P < 0.01) excretion, as well as blunted the decrease in resting (CON: −6 ± 2 bpm; KE: +2 ± 3 bpm, P < 0.05), submaximal (CON: −15 ± 3 bpm; KE: −7 ± 2 bpm, P < 0.05) and maximal (CON: −17 ± 2 bpm; KE: −10 ± 2 bpm, P < 0.01) heart rate. Energy balance during the training period spontaneously turned negative in CON (−2135 kJ/day), but not in KE (+198 kJ/day). The training consistently increased growth differentiation factor 15 (GDF15), but ∼2‐fold more in CON than in KE ( P < 0.05). In addition, delta GDF15 correlated with the training‐induced drop in maximal heart rate ( r = 0.60, P < 0.001) and decrease in osteocalcin ( r = 0.61, P < 0.01). Other measurements such as blood ACTH, cortisol, IL‐6, leptin, ghrelin and lymphocyte count, and muscle glycogen content did not differentiate KE from CON. In conclusion, KE during strenuous endurance training attenuates the development of overreaching. We also identify GDF15 as a possible marker of overtraining.

          Key points

          • Overload training is required for sustained performance gain in athletes (functional overreaching). However, excess overload may result in a catabolic state which causes performance decrements for weeks (non‐functional overreaching) up to months (overtraining).

          • Blood ketone bodies can attenuate training‐ or fasting‐induced catabolic events. Therefore, we investigated whether increasing blood ketone levels by oral ketone ester (KE) intake can protect against endurance training‐induced overreaching.

          • We show for the first time that KE intake following exercise markedly blunts the development of physiological symptoms indicating overreaching, and at the same time significantly enhances endurance exercise performance.

          • We provide preliminary data to indicate that growth differentiation factor 15 (GDF15) may be a relevant hormonal marker to diagnose the development of overtraining.

          • Collectively, our data indicate that ketone ester intake is a potent nutritional strategy to prevent the development of non‐functional overreaching and to stimulate endurance exercise performance.

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          Most cited references71

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          Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

          The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.
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            Prevention, diagnosis, and treatment of the overtraining syndrome: joint consensus statement of the European College of Sport Science and the American College of Sports Medicine.

            Successful training not only must involve overload but also must avoid the combination of excessive overload plus inadequate recovery. Athletes can experience short-term performance decrement without severe psychological or lasting other negative symptoms. This functional overreaching will eventually lead to an improvement in performance after recovery. When athletes do not sufficiently respect the balance between training and recovery, nonfunctional overreaching (NFOR) can occur. The distinction between NFOR and overtraining syndrome (OTS) is very difficult and will depend on the clinical outcome and exclusion diagnosis. The athlete will often show the same clinical, hormonal, and other signs and symptoms. A keyword in the recognition of OTS might be "prolonged maladaptation" not only of the athlete but also of several biological, neurochemical, and hormonal regulation mechanisms. It is generally thought that symptoms of OTS, such as fatigue, performance decline, and mood disturbances, are more severe than those of NFOR. However, there is no scientific evidence to either confirm or refute this suggestion. One approach to understanding the etiology of OTS involves the exclusion of organic diseases or infections and factors such as dietary caloric restriction (negative energy balance) and insufficient carbohydrate and/or protein intake, iron deficiency, magnesium deficiency, allergies, and others together with identification of initiating events or triggers. In this article, we provide the recent status of possible markers for the detection of OTS. Currently, several markers (hormones, performance tests, psychological tests, and biochemical and immune markers) are used, but none of them meet all the criteria to make their use generally accepted.
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              Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1.

              Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.
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                Author and article information

                Contributors
                peter.hespel@kuleuven.be
                Journal
                J Physiol
                J. Physiol. (Lond.)
                10.1111/(ISSN)1469-7793
                TJP
                jphysiol
                The Journal of Physiology
                John Wiley and Sons Inc. (Hoboken )
                0022-3751
                1469-7793
                22 May 2019
                15 June 2019
                22 May 2019
                : 597
                : 12 ( doiID: 10.1113/tjp.2019.597.issue-12 )
                : 3009-3027
                Affiliations
                [ 1 ] Exercise Physiology Research Group Department of Movement Sciences KU Leuven Leuven Belgium
                [ 2 ] Bakala Academy‐Athletic Performance Center KU Leuven Leuven Belgium
                Author notes
                [*] [* ] Corresponding author P. Hespel: Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Tervuursevest 101, Heverlee, 3001, Belgium. Email:  peter.hespel@ 123456kuleuven.be
                Author information
                https://orcid.org/0000-0003-1283-2229
                Article
                TJP13540
                10.1113/JP277831
                6851819
                31039280
                b044785e-6254-4b1f-b2ed-21df46bca1a6
                © 2019 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 March 2019
                : 25 April 2019
                Page count
                Figures: 10, Tables: 5, Pages: 19, Words: 12373
                Funding
                Funded by: Research Fund Flanders (Fonds voor Wetenschappelijk Onderzoek – Vlaanderen
                Award ID: G080117N
                Categories
                Research Paper
                Exercise
                Editor's Choice
                Custom metadata
                2.0
                15 June 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:13.11.2019

                Human biology
                ketone,overreaching and overtraining,exercise recovery,gdf15
                Human biology
                ketone, overreaching and overtraining, exercise recovery, gdf15

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