Exercise tolerance is impaired in hypoxia, and it has recently been shown that dietary nitrate supplementation can reduce the oxygen (O(2)) cost of muscle contractions. Therefore, we investigated the effect of dietary nitrate supplementation on arterial, muscle, and cerebral oxygenation status, symptoms of acute mountain sickness (AMS), and exercise tolerance at simulated 5,000 m altitude. Fifteen young, healthy volunteers participated in three experimental sessions according to a crossover study design. From 6 days prior to each session, subjects received either beetroot (BR) juice delivering 0.07 mmol nitrate/kg body wt/day or a control drink (CON). One session was in normoxia with CON (NOR(CON)); the two other sessions were in hypoxia (11% O(2)), with either CON (HYP(CON)) or BR (HYP(BR)). Subjects first cycled for 20 min at 45% of peak O(2) consumption (VO(2)peak; EX(45%)) and thereafter, performed a maximal incremental exercise test (EX(max)). Whole-body VO(2), arterial O(2) saturation (%SpO(2)) via pulsoximetry, and tissue oxygenation index of both muscle (TOI(M)) and cerebral (TOI(C)) tissue by near-infrared spectroscopy were measured. Hypoxia per se substantially reduced VO(2)peak, %SpO(2), TOI(M), and TOI(C) (NOR(CON) vs. HYP(CON), P < 0.05). Compared with HYP(CON), VO(2) at rest and during EX(45%) was lower in HYP(BR) (P < 0.05), whereas %SpO(2) was higher (P < 0.05). TOI(M) was ~4-5% higher in HYP(BR) than in HYP(CON) both at rest and during EX(45%) and EX(max) (P < 0.05). TOI(C) as well as the incidence of AMS symptoms were similar between HYP(CON) and HYP(BR) at any time. Hypoxia reduced time to exhaustion in EX(max) by 36% (P < 0.05), but this ergolytic effect was partly negated by BR (+5%, P < 0.05). Short-term dietary nitrate supplementation improves arterial and muscle oxygenation status but not cerebral oxygenation status during exercise in severe hypoxia. This is associated with improved exercise tolerance against the background of a similar incidence of AMS.

In humans, nutrient deprivation and extreme endurance exercise both activate autophagy. We hypothesized that cumulating fasting and cycling exercise would potentiate activation of autophagy in skeletal muscle. Well-trained athletes were divided into control (n = 8), low-intensity (LI, n = 8), and high-intensity (HI, n = 7) exercise groups and submitted to fed and fasting sessions. Muscle biopsy samples were obtained from the vastus lateralis before, at the end, and 1 h after a 2 h LI or HI bout of exercise. Phosphorylation of ULK1 Ser317 was higher after exercise (P < 0.001). In both the fed and the fasted states, LC3bII protein level and LC3bII/I were decreased after LI and HI (P < 0.05), while p62/ SQSTM1 was decreased only 1 h after HI (P < 0.05), indicating an increased autophagic flux after HI. The autophagic transcriptional program was also activated, as evidenced by the increased level of LC3b, p62/ SQSTM1, GabarapL1, and Cathepsin L mRNAs observed after HI but not after LI. The increased autophagic flux after HI exercise could be due to increased AMPactivated protein kinase a (AMPKa) activity, as both AMPKa Thr172 and ACC Ser79 had a higher phosphorylation state after HI (P < 0.001). In summary, the most effective strategy to activate autophagy in human skeletal muscle seems to rely on exercise intensity more than diet.-Schwalm, C., Jamart, C., Benoit, N., Naslain, D., Prémont, C., Prévet, J., Van Thienen, R., Deldicque, L., Francaux, M. Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation. FASEB J. 29, 3515-3526 (2015). www.fasebj.org

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.

Oral betaALA supplementation can significantly enhance sprint performance at the end of an exhaustive endurance exercise bout.

Purpose: Ketone bodies are energy substrates produced by the liver during prolonged fasting or low-carbohydrate diet. The ingestion of a ketone ester (KE) rapidly increases blood ketone levels independent of nutritional status. KE has recently been shown to improve exercise performance, but whether it can also promote post-exercise muscle protein or glycogen synthesis is unknown.Methods: Eight healthy trained males participated in a randomized double-blind placebo-controlled crossover study. In each session, subjects undertook a bout of intense one-leg glycogen-depleting exercise followed by a 5-h recovery period during which they ingested a protein/carbohydrate mixture. Additionally, subjects ingested a ketone ester (KE) or an isocaloric placebo (PL).Results: KE intake did not affect muscle glycogen resynthesis, but more rapidly lowered post-exercise AMPK phosphorylation and resulted in higher mTORC1 activation, as evidenced by the higher phosphorylation of its main downstream targets S6K1 and 4E-BP1. As enhanced mTORC1 activation following KE suggests higher protein synthesis rates, we used myogenic C2C12 cells to further confirm that ketone bodies increase both leucine-mediated mTORC1 activation and protein synthesis in muscle cells.Conclusion: Our results indicate that adding KE to a standard post-exercise recovery beverage enhances the post-exercise activation of mTORC1 but does not affect muscle glycogen resynthesis in young healthy volunteers. In vitro, we confirmed that ketone bodies potentiate the increase in mTORC1 activation and protein synthesis in leucine-stimulated myotubes. Whether, chronic oral KE intake during recovery from exercise can facilitate training-induced muscular adaptation and remodeling need to be further investigated.