Reply from Chiel Poffé, Monique Ramaekers and Peter Hespel

We appreciate the interest of P. Bellinger in our recent article in which we reported that ketone ester (KE) intake blunts the development of overreaching symptoms and stimulates endurance exercise performance (Poffé et al. 2019a). In his Letter to the Editor, Bellinger states that our conclusion that KE blunts the development of overreaching symptoms is unfounded, as the subjects were not in a state of non-functional overreaching (NFOR) but were only functionally overreached (FOR) (Bellinger, 2019). The author substantiates his commentary by (intentionally) omitting a crucial part of the definition of NFOR as proposed in the consensus statement of the European College of Sport Science and the American College of Sports Medicine (Meeusen et al. 2013). We respectfully disagree with Bellinger’s statements as our conclusions are independent of whether or not NFOR occurred, but are based on the observation that physiological symptoms indicative of the development of NFOR were clearly blunted by KE. Moreover, we argue that any discussion about whether subjects were either FOR or NFOR is simply nonsensical as there are no objective criteria to discriminate between both at the individual level. Finally, our study did not at all intend to identify symptoms from which NFOR could be diagnosed. We wanted to isolate symptoms and explore the effect of KE intake here on, which in a longitudinal follow-up of an athlete would allow the transition from FOR to NFOR to be identified, in order to provide a timely reduction in training load. Bellinger correctly states that FOR results in a short-term decrease in performance, in which restoration of performance may take days to weeks. However, the author states that NFOR causes a decrease in performance that will not resume for several weeks or months, thereby neglecting that a stagnation of performance may also indicate NFOR (Meeusen et al. 2013). Therefore, the observed absence of improvements in the 30 min time-trial and 90 s sprint performance in some subjects following seven rest days does not justify the claim by Bellinger that all subjects were merely FOR. But again, in fact, this does not even matter in the context of the current study. In a second point, the author states that subjects should be classified on an individual basis as FOR or NFOR, and that such a classification is typically employed in other studies while completely lacking in our manuscript. We completely agree that such a classification would be highly desirable. However, although cross-sectional studies have suggested criteria to discriminate between NFOR and the overtraining syndrome (Meeusen et al. 2004, 2010; Buyse et al. 2019), clear-cut criteria to adequately discriminate FOR from NFOR are entirely missing. In fact, not a single published paper, including those cited by Bellinger, has been able to make such a distinction at the individual level. Therefore, we believe that it would be inappropriate to classify each subject as either FOR or NFOR based on unvalidated criteria. However, in agreement with the aforementioned consensus statement (Meeusen et al. 2013), we indicated in our article that in the total group of subjects both FOR and NFOR were indeed present. Following 7 days of recovery, performance was still decreased in some versus increased in others (90 s sprint: −5 to +13%; 30 min time-trial: −5 to +14%). Adequate prevention of NFOR requires pertinent longitudinal follow-up of an athlete. Therefore, and also from a purely scientific perspective, it is bizarre that Bellinger challenges our longitudinal findings based on earlier cross-sectional observations. For sure, identification of adequate markers indicating transition from FOR to NFOR will require more well-controlled longitudinal studies to be done. Given the inability to discriminate objectively between FOR and NFOR, the argument by Bellinger that growth differentiation factor 15 (GDF15) levels should be studied in response to an individual’s classification to serve as a marker for the development of overreaching/overtraining does not make sense. Only longitudinal observations can really serve such a purpose. Therefore, we believe that (i) the consistent increase in GDF15 with training overload in all subjects, (ii) the divergent response in GDF15 between the less (KE) versus the more overreached (control) group, and (iii) the strong correlation between GDF15 and the training-induced drop in peak exercise heart rate clearly document the potential of GDF15 to serve as a biological marker of the degree of overreaching in a given individual. However, more longitudinal studies are needed to support such a statement, of course. Notwithstanding the above debate, the aim of our study was not to diagnose whether NFOR occurred, but to investigate in a hands-on approach whether KE intake could blunt the development of overreaching symptoms, thereby allowing higher training volumes to be tolerated. Therefore, we employed an ecologically valid study design by imposing a ‘supramaximal’ training load to induce failure in adherence to the prescribed training programme. This resulted in higher training loads for subjects receiving ketone supplements. Nonetheless, subjects from the KE group exhibited remarkably fewer symptoms indicating overreaching development. These data clearly indicate that KE intake is a potent nutritional strategy to reduce the incidence of overreaching symptoms, independent of whether or not a subject is classified as FOR or NFOR. In a final point, Bellinger argues that the 15% increase in 30 min time-trial performance following a 90 min preload (EPT120min) at day 18 of the training period observed in KE might be the result of initial between-group differences. We fully agree that this cannot be excluded. However, the ability of KE subjects to manage a 15% higher training load at the end of the training period, together with the pair-matched study design, provide strong arguments to believe that these between-group differences are indeed merely caused by the experimental conditions. Nevertheless, as indicated in our reply to Korevaar et al. (Poffé et al. 2019b), we predefined only training load as the primary endpoint. Therefore, the conclusion that KE intake stimulates endurance performance is primarily based on the differences in training load, but it is further supported by alterations in other performance tests (90 s sprint, 30 min time-trial, EPT120min), as already shown in