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Journal: The Journal of physiology


We investigated the effects of adaptation to a ketogenic low-carbohydrate (CHO), high-fat diet (LCHF) during 3 wk of intensified training on metabolism and performance of world-class endurance athletes. We controlled three isoenergetic diets in elite race walkers: High CHO availability (8.6 1.d(-1) CHO, 2.1 1.d(-1) protein; 1.2 1.d(-1) fat) consumed before/during/after training (HCHO, n = 9): identical macronutrient intake, periodised within/between days to alternate between low and high CHO availability (PCHO, n = 10); LCHF (<50 g.d(-1) CHO; 78% energy as fat; 2.1 1.d(-1) protein; LCHF, n = 10). Post-intervention, VO2 peak during race walking increased in all groups (P < 0.001, 90%CI: [2.55 - 5.20%]). LCHF was associated with markedly increased rates of whole-body fat oxidation, attaining peak rates of 1.57 ± 0.32 g.min(-1) during 2 h of walking at ∼80%VO2 peak. However, LCHF also increased the oxygen (O2 ) cost of race walking at velocities relevant to real-life race performance: O2 uptake (expressed as % of new VO2peak ) at a speed approximating 20 km race pace was reduced in HCHO and PCHO (90%CI:[-7.047;-2.55] and [-5.18;-0.86], respectively, but was maintained at pre-intervention levels in LCHF. HCHO and PCHO groups improved times for 10 km race walk: 6.6% (90% CI: [4.1; 9.1%]) and 5.3% [3.4; 7.2%], with no improvement (-1.6% [-8.5; 5.3%] for the LCHF group. In contrast to training with diets providing chronic or periodised high-CHO availability, and despite a significant improvement in VO2peak , adaptation to the topical LCHF diet negated performance benefits in elite endurance athletes, in part, due to reduced exercise economy. This article is protected by copyright. All rights reserved.

Concepts: Ketosis, Racewalking, Carbohydrate, Low-carbohydrate diet, Metabolism, Walking, Ketogenic diet, Nutrition


Aerobic exercise such as running enhances adult hippocampal neurogenesis (AHN) in rodents. Little is known about the effects of high-intensity interval training (HIT) or of purely anaerobic resistance training on AHN. Here, compared to a sedentary lifestyle, we report a very modest effect of HIT and no effect of resistance training on AHN in adult male rats. We find most AHN in rats that were selectively bred for an innately high response to aerobic exercise that also run voluntarily and - increase maximum running capacity. Our results confirm that sustained aerobic exercise is key in improving AHN.

Concepts: Cycling, Running, Overweight, Obesity, Exercise physiology, Weight training, Strength training, Exercise


When using our arms to interact with the world, unintended body motion can introduce movement error. A mechanism which could detect and compensate for such motion would be beneficial. Observations of arm movements evoked by vestibular stimulation provide some support for this mechanism. However, the physiological function underlying these artificially-evoked movements is unclear from previous research. For such a mechanism to be functional, it should only operate when the arm is being controlled in an earth-fixed rather than body-fixed reference frame. In the latter case, compensation would be unnecessary and even deleterious. To test this hypothesis, subjects were gently rotated in a chair while asked to maintain their outstretched arm pointing either towards earth-fixed (EF) or body-fixed (BF) memorised targets. Galvanic vestibular stimulation (GVS) was applied concurrently during rotation to isolate the influence of vestibular input, uncontaminated by inertial factors. During the EF task, GVS produced large polarity-dependent corrections in arm position. These corrections mimicked those evoked when chair velocity was altered without any GVS, indicating a compensatory arm response to a sensation of altered body motion. In stark contrast, corrections were completely absent during the BF task, despite the same chair movement profile and arm posture. These effects persisted when we controlled for differences in limb kinematics between the two tasks. Our results demonstrate that vestibular control of the upper-limb maintains reaching accuracy during unpredictable body motion. The observation that such responses only occurred when reaching within an EF reference frame confirms the functional nature of vestibular-evoked arm movement. This article is protected by copyright. All rights reserved.

Concepts: Special relativity, Frame of reference, Scientific method, Observation, Classical mechanics, Copyright, Galvanic Vestibular Stimulation, Vestibular system


A ketogenic diet is known to lead to weight loss and is considered metabolically healthy; however there are conflicting reports on its effect on hepatic insulin sensitivity. KD fed animals appear metabolically healthy in the fasted state after 3 days of dietary challenge, whereas obesogenic high-fat diet (HFD) fed animals show elevated insulin levels. A glucose challenge reveals that both KD and HFD fed animals are glucose intolerant. Glucose intolerance correlates with increased lipid oxidation and lower respiratory exchange ratio (RER); however, all animals respond to glucose injection with an increase in RER. Hyperinsulinaemic-euglycaemic clamps with double tracer show that the effect of KD is a result of hepatic insulin resistance and increased glucose output but not impaired glucose clearance or tissue glucose uptake in other tissues.


Sarcopenia results from the progressive loss of skeletal muscle mass and reduced function in older age. It is likely to be associated with the well-documented reduction of motor unit numbers innervating limb muscles and the increase in size of surviving motor units via reinnervation of denervated fibres. However no evidence currently exists to confirm the extent of motor unit remodelling in sarcopenic individuals. The aim of the present study was to compare motor unit size and number between young (n = 48), non-sarcopenic old (n = 13), pre-sarcopenic (n = 53) and sarcopenic (n = 29) men. Motor unit potentials (MUPs) were isolated from intramuscular and surface electromyographic recordings. The motor unit numbers were reduced in all groups of old compared with young (all P < 0.001). Motor unit potentials were enlarged in non-sarcopenic and pre-sarcopenic men compared with young (P = 0.039 and 0.001 respectively), but not in the VL of sarcopenic old (P = 0.485). The results suggest that extensive motor unit remodelling occurs relatively early during ageing, exceeds the loss of muscle mass and precedes sarcopenia. Reinnervation of denervated muscle fibres likely expands the motor unit size in non-sarcopenic and pre-sarcopenic old, but not in the sarcopenic old. These findings suggest that a failure to expand the motor unit size distinguishes sarcopenic from pre-sarcopenic muscles. This article is protected by copyright. All rights reserved.

Concepts: Electromyography, Myosin, Sarcopenia, Muscular system, Glycogen, Muscle atrophy, Cardiac muscle, Muscle


Vascular function and arterial stiffness are important markers of cardiovascular health and cardiovascular co-morbidity. Transitional phases of hypoemia and hypermia, with consequent fluctuations in shear rate, occuring during repetitive passive stretching adminstration (passive stretching training) may constitute an effective stimulus to induce an amelioration in vascular function, arterial stiffness and vascular remodelling by improving central and local blood flow control mechanisms. Vascular function, arterial stiffness and vascular remodelling were evaluated before and after 12 weeks of passive stretching training and after 6 weeks from training cessation, in the femoral, popliteal (treated with stretching), and brachial arteries (untreated) of both sides. After passive stretching training, vascular function and arterial remodelling improved, and arterial stiffness decreased in all the arteries, suggesting modifications of both central and local blood flow control mechanisms. Passive stretching-induced improvements related to central mechanisms seemed to have a short duration, as they returned to pre-training baseline within 6 weeks from training cessation, whereas those more related to a local mechanism persisted in the follow-up.


Central arterial stiffness increases with sedentary aging. While near-daily, vigorous lifelong (>25 yr) endurance exercise training prevents arterial stiffening with aging, this rigorous routine of exercise training over a lifetime is impractical for most individuals. The aim was to examine whether a less frequent ‘dose’ of lifelong exercise training (4-5 sessions/wk for > 30 min) that is consistent with current physical activity recommendations elicits similar benefits on central arterial stiffening with aging. A cross-sectional examination of 102 seniors (>60 yrs old), who had a consistent lifelong exercise history was performed. Subjects were stratified into 4 groups based on exercise frequency as an index of exercise ‘dose’: sedentary: < 2 sessions/wk; casual exercisers: 2-3 sessions/wk; committed exercisers: 4-5 sessions/wk; Masters athletes: 6-7 sessions/wk plus regular competitions. Detailed measures of arterial stiffness and left ventricular afterload were collected. Biological aortic age and central PWV were younger in committed exercisers and Masters athletes compared to sedentary seniors. TACi (total arterial compliance) was lower, while Carotid β-stiffness index and Eai (effective arterial elastance) were higher in sedentary seniors compared to the other groups. There appeared to be a dose-response threshold for carotid β-stiffness index and TACi. Peripheral arterial stiffness was not significantly different among the groups. These data suggest that 4-5 weekly exercise sessions over a lifetime is associated with reduced central arterial stiffness in the elderly. A less frequent dose of lifelong exercise (2-3 sessions/wk) is associated with decreased ventricular afterload and peripheral resistance, while peripheral arterial stiffness is unaffected by any dose of exercise. This article is protected by copyright. All rights reserved.


This experiment assessed molecular responses of human subcutaneous abdominal adipose tissue (SCAT) to 6 weeks of morning fasting. Forty-eight, healthy lean (n = 29) and obese (n = 20) adults provided SCAT biopsies before and after six weeks of morning fasting (FAST; 0 kcal until 1200 h) or daily breakfast consumption (BFAST; ≥700 kcal before 1100 h). Biopsies were analysed for mRNA levels of selected genes, and GLUT4 and Akt protein content. Basal and insulin-stimulated Akt activation and tissue glucose uptake rates were also determined. In lean individuals, lipid turnover and insulin signalling genes (ACADM and IRS2) were upregulated with FAST versus BFAST [1.14 (95%CI: 0.97 to 1.30) versus 0.80 (95%CI: 0.64 to 0.96), P = 0.007 and 1.75 (95%CI: 1.33 to 2.16) versus 1.09 (95%CI: 0.67 to 1.51), P = 0.03, respectively). In obese individuals, no differential (FAST versus BFAST) expression was observed in genes involved in lipid turnover (all P > 0.1). GLUT4, Akt protein content and insulin-stimulated Akt phosphorylation were unaffected by FAST versus BFAST in both lean and obese cohorts (all P > 0.1). Lower insulin-stimulated glucose uptake rates in obese versus lean individuals were eradicated when normalised to whole-body fat mass (P = 0.416). We conclude that morning fasting upregulates lipid turnover genes in SCAT of lean individuals. Secondly, altered SCAT insulin sensitivity with morning fasting is unlikely to be explained by signalling proximal to Akt. Finally, lower insulin-stimulated SCAT glucose uptake rates in obese individuals are proportional to whole-body fat mass, suggesting a compensatory downregulation, presumably to prevent excessive de novo lipogenesis in adipose tissue. This trial was registered as ISRCTN31521726. This article is protected by copyright. All rights reserved.

Concepts: Nutrition, AKT, Protein, Fat, Insulin resistance, Insulin, Obesity, Adipose tissue


Adolescence encompasses a sensitive developmental period of enhanced clinical vulnerability to nicotine, tobacco, and e-cigarettes. While there are sociocultural influences, data at preclinical and clinical levels indicate that this adolescent sensitivity has strong neurobiological underpinnings. Although definitions of adolescence vary, the hallmark of this period is a profound reorganization of brain regions necessary for mature cognitive and executive function, working memory, reward processing, emotional regulation, and motivated behavior. Regulating critical facets of brain maturation are nicotinic acetylcholine receptors (nAChRs). However, perturbations of cholinergic systems during this time with nicotine, via tobacco or e-cigarettes, have unique consequences on adolescent development. In this review, we highlight recent clinical and preclinical data examining the adolescent brain’s distinct neurobiology and unique sensitivity to nicotine. First, we discuss what defines adolescence before reviewing normative structural and neurochemical alterations that persist until early adulthood, with an emphasis on dopaminergic systems. We review how acute exposure to nicotine impacts brain development and how drug responses differ from those seen in adults. Finally, we discuss the persistent alterations in neuronal signaling and cognitive function that result from chronic nicotine exposure, while highlighting a low dose, semi-chronic exposure paradigm that may better model adolescent tobacco use. We argue that nicotine exposure, increasingly occurring as a result of e-cigarette use, may induce epigenetic changes that sensitize the brain to other drugs and prime it for future substance abuse.

Concepts: Electronic cigarette, Neurotransmitter, Nervous system, Tobacco, Psychology, Nicotinic acetylcholine receptor, Acetylcholine, Nicotine


Advanced maternal age (≥35 years) is associated with increased rates of operative delivery, stillbirth, and post-term labour induction. The physiological causes remain uncertain, although impaired myometrial function has been implicated. To investigate the hypothesis that maternal age directly influences successful parturition, we assessed the timing of birth and fetal outcome in pregnant C57BL/6J mice at 3 months (young), 5 (intermediate) months vs. 8 months (older) of age using infra-red video recording. Serum progesterone profiles, myometrium and cervix function, and mitochondrial electron transport chain complex enzymatic activities were also examined. Older pregnant mice had longer mean gestation and labour duration (P <  0.001), as well as reduced litter size (P <  0.01) vs. 3 month old mice. Older mice did not exhibit the same decline in serum progesterone concentrations as younger mice. Cervical tissues from older mice were more distensible than younger mice (P <  0.05). Oxytocin receptor and connexin-43 mRNA expression were reduced in myometrium from 8 month vs. 3 month old mice (P <  0.05, P <  0.01 respectively) in tandem with more frequent, but shorter duration spontaneous myometrial contractions (P <  0.05) and an attenuated contractile response to oxytocin. Myometrial mitochondrial copy number was reduced in older mice, but there were no age-induced changes to the enzymatic activities of the mitochondrial electron transport chain complexes. In conclusion, 8 month old mice provide a useful model of reproductive ageing. This study has identified potential causes of labour dysfunction amenable to investigation in older primigravid women. This article is protected by copyright. All rights reserved.

Concepts: Photosynthesis, Cellular respiration, Reactive oxygen species, Oxytocin, Adenosine triphosphate, Pregnancy, Uterus, Childbirth