Acute high-intensity interval running increases markers of damage and permeability but not gastrointestinal symptoms.

Purpose: To investigate the effects of high-intensity interval (HIIT) running on markers of gastrointestinal (GI) damage and permeability alongside subjective symptoms of GI discomfort. Methods: Eleven male runners completed an acute bout of HIIT (eighteen 400 m runs at 120%O2max ) where markers of GI permeability, intestinal damage and GI discomfort symptoms were assessed and compared with resting conditions. Results: Compared to rest, HIIT significantly increased serum lactulose:rhamnose ratio (0.051 ± 0.016 vs. 0.031 ± 0.021, p = 0.0047; 95% CI = 0.006 - 0.036) and sucrose concentrations (0.388 ± 0.217 vs 0.137 ± 0.148 mg.l-1; p < 0.001; 95% CI = 0.152 - 0.350). In contrast, urinary lactulose:rhamnose (0.032 ± 0.005 vs 0.030 ± 0.005; p = 0.3; 95% CI = -0.012 - 0.009) or sucrose concentrations (0.169 ± 0.168% vs 0.123 ± 0.120%; p = 0.54; 95% CI = -0.199 - 0.108) did not differ between HIIT and resting conditions. Plasma I-FABP was significantly increased (p < 0.001) during and in the recovery period from HIIT whereas no changes were observed during rest. Mild-symptoms of GI discomfort, were reported immediately- and 24 h post-HIIT, although these symptoms did not correlate to GI permeability or I-FABP. Conclusion Acute HIIT increased GI permeability and intestinal I-FABP release, although these do not correlate with symptoms of GI discomfort. Furthermore, by using serum sampling, we provide data showing that it is possible to detect changes in intestinal permeability that is not observed using urinary sampling over a shorter time-period

Fuel for the Work Required: A Theoretical Framework for Carbohydrate Periodization and the Glycogen Threshold Hypothesis.

Deliberately training with reduced carbohydrate (CHO) availability to enhance endurance-training-induced metabolic adaptations of skeletal muscle (i.e. the 'train low, compete high' paradigm) is a hot topic within sport nutrition. Train-low studies involve periodically training (e.g., 30-50% of training sessions) with reduced CHO availability, where train-low models include twice per day training, fasted training, post-exercise CHO restriction and 'sleep low, train low'. When compared with high CHO availability, data suggest that augmented cell signalling (73% of 11 studies), gene expression (75% of 12 studies) and training-induced increases in oxidative enzyme activity/protein content (78% of 9 studies) associated with 'train low' are especially apparent when training sessions are commenced within a specific range of muscle glycogen concentrations. Nonetheless, such muscle adaptations do not always translate to improved exercise performance (e.g. 37 and 63% of 11 studies show improvements or no change, respectively). Herein, we present our rationale for the glycogen threshold hypothesis, a window of muscle glycogen concentrations that simultaneously permits completion of required training workloads and activation of the molecular machinery regulating training adaptations. We also present the 'fuel for the work required' paradigm (representative of an amalgamation of train-low models) whereby CHO availability is adjusted in accordance with the demands of the upcoming training session(s). In order to strategically implement train-low sessions, our challenge now is to quantify the glycogen cost of habitual training sessions (so as to inform the attainment of any potential threshold) and ensure absolute training intensity is not compromised, while also creating a metabolic milieu conducive to facilitating the endurance phenotype

Whey Protein Augments Leucinemia and Post-Exercise p70S6K1 Activity Compared to a Hydrolysed Collagen Blend When in Recovery From Training With Low Carbohydrate Availability

We examined the effects of whey versus collagen protein on skeletal muscle cell signalling responses associated with mitochondrial biogenesis and protein synthesis in recovery from an acute training session completed with low carbohydrate (CHO) availability. In a repeated measures design (after adhering to a 36-h exercise-dietary intervention to standardise pre-exercise muscle glycogen), eight males completed a 75-min non-exhaustive cycling protocol and consumed 22 g of a hydrolysed collagen blend (COLLAGEN) or whey (WHEY) protein 45 min prior to exercise, 22 g during exercise and 22 g immediately post-exercise. Exercise decreased (P0.05) was observed for p53, Parkin and Beclin1 mRNA. Exercise suppressed (P<0.05) p70S6K1 activity in both conditions immediately post-exercise (≈ 25 fmol.min-1.mg-1). Post-exercise feeding increased p70S6K1 activity at 1.5 h post-exercise (P<0.05), the magnitude of which was greater (P <0.05) in WHEY (180 ± 105 fmol.min-1.mg-1) versus COLLAGEN (73 ± 42 fmol.min-1.mg-1). We conclude that protein composition does not modulate markers of mitochondrial biogenesis when in recovery from a training session deliberately completed with low CHO availability. In contrast, whey protein augments post-exercise p70S6K activity compared with hydrolysed collagen, as likely mediated via increased leucine availability

Metabolic demands and replenishment of muscle glycogen after a rugby league match simulation protocol.

OBJECTIVES: The metabolic requirements of a rugby league match simulation protocol and the timing of carbohydrate provision on glycogen re-synthesis in damaged muscle were examined. DESIGN: Fifteen (mean±SD: age 20.9±2.9 year, body-mass 87.3±14.1kg, height 177.4±6.0cm) rugby league (RL) players consumed a 6gkgday-1 CHO diet for 7-days, completed a time to exhaustion test (TTE) and a glycogen depletion protocol on day-3, a RL simulated-match protocol (RLMSP) on day-5 and a TTE on day-7. Players were prescribed an immediate or delayed (2-h-post) re-feed post-simulation. METHODS: Muscle biopsies and blood samples were obtained post-depletion, before and after simulated match-play, and 48-h after match-play with PlayerLoad and heart-rate collected throughout the simulation. Data were analysed using effects sizes±90% CI and magnitude-based inferences. RESULTS: PlayerLoad (8.0±0.7 AUmin-1) and %HRpeak (83±4.9%) during the simulation were similar to values reported for RL match-play. Muscle glycogen very likely increased from immediately after to 48-h post-simulation (272±97 cf. 416±162mmolkg-1d.w.; ES±90%CI) after immediate re-feed, but changes were unclear (283±68 cf. 361±144mmolkg-1d.w.; ES±90%CI) after delayed re-feed. CK almost certainly increased by 77.9±25.4% (0.75±0.19) post-simulation for all players. CONCLUSIONS: The RLMSP presents a replication of the internal loads associated with professional RL match-play, although difficulties in replicating the collision reduced the metabolic demands and glycogen utilisation. Further, it is possible to replete muscle glycogen in damaged muscle employing an immediate re-feed strategy

Glycogen Utilization during Running: Intensity, Sex, and Muscle-specific Responses.

PURPOSE: To quantify net glycogen utilisation in the vastus lateralis (VL) and gastrocnemius (G) of male (n=11) and female (n=10) recreationally active runners during three outdoor training sessions. METHODS: After 2 days standardisation of carbohydrate (CHO) intakes (6 g.kg body mass per day), glycogen was assessed before and after 1) a 10-mile road run (10-mile) at lactate threshold, 2) 8 x 800 m track intervals (8 x 800 m) at velocity at V[Combining Dot Above]O2max and 3) 3 x 10 minute track intervals (3 x 10 min) at lactate turnpoint. RESULTS: Resting glycogen concentration was lower in the G of females compared with males (P0.05). Net glycogen utilisation was greater in males than females in both VL (P=0.02) and G (P=0.07) during the 10-mile road run. With the exception of males during the 3 x 10 min protocol (P=0.28), greater absolute glycogen utilisation was observed in the G versus the VL muscle in both males and females and during all training protocols (all comparisons, P<0.05). CONCLUSION: Data demonstrate 1) prolonged steady state running necessitates a greater glycogen requirement than shorter but higher intensity track running sessions, 2) females display evidence of reduced resting muscle glycogen concentration and net muscle glycogen utilisation when compared with males and 3), net glycogen utilisation is higher in the gastrocnemius muscle compared with the vastus lateralis

A pilot sequential multiple assignment randomized trial (SMART) protocol for developing an adaptive coaching intervention around a mobile application for athletes to improve carbohydrate periodization behavior.

Background: It has recently been identified that manipulating carbohydrate availability around exercise activity can enhance training-induced metabolic adaptations. Despite this approach being accepted in the athletic populations, athletes do not systematically follow the guidelines. Digital environments appear to allow nutritionists to deliver this intervention at scale, reducing expensive human coaching time. Yet, digitally delivered dietary behavior change interventions for athletes and the coaching strategy to support them are still novel concepts within sports nutrition. Methods/design: We aim to recruit 900 athletes across the UK. 500 athletes will be recruited to test the feasibility of a novel menu planner mobile application with coaching for 6 weeks. 250 athletes with pre-existing nutritionist support will also be recruited as control. We will then conduct a 4-week pilot sequential multiple assignment randomized trial (SMART) with an additional 150 athletes. In the SMART, athletes will be given the application and additional coaching according to their engagement responses. The primary outcomes are the mobile application and coach uptake, retention, engagement, and success in attaining carbohydrate periodization behavior. Secondary outcomes are changes in goal, weight, carbohydrate periodization self-efficacy, and beliefs about consequences. Due to the high attrition nature of digital interventions, all quantitative analyses will be carried out based on both the intention-to-treat and per-protocol principles. Discussion: This study will be the first to investigate improving carbohydrate periodization using a digital approach and tailored coaching strategies under this context. Foundational evidence from this study will provide insights into the feasibility of the digital approach

Collision activity during training increases total energy expenditure measured via doubly labelled water

Purpose: Collision sports are characterised by frequent high intensity collisions that induce substantial muscle damage, potentially increasing the energetic cost of recovery. Therefore, this study investigated the energetic cost of collision-based activity for the first time across any sport. Methods: Using a randomised crossover design, six professional young male rugby league players completed two different five-day pre-season training microcycles. Players completed either a collision (COLL; 20 competitive one-on-one collisions) or non-collision (nCOLL; matched for kinematic demands, excluding collisions) training session on the first day of each microcycle, exactly seven days apart. All remaining training sessions were matched and did not involve any collision-based activity. Total energy expenditure was measured using doubly labelled water, the literature gold standard. Results: Collisions resulted in a very likely higher (4.96 ± 0.97 MJ; ES = 0.30 ±0.07; p=0.0021) total energy expenditure across the five-day COLL training microcycle (95.07 ± 16.66 MJ) compared with the nCOLL training microcycle (90.34 ± 16.97 MJ). The COLL training session also resulted in a very likely higher (200 ± 102 AU; ES = 1.43 ±0.74; p=0.007) session rating of perceived exertion and a very likely greater (-14.6 ± 3.3%; ES = -1.60 ±0.51; p=0.002) decrease in wellbeing 24h later. Conclusions: A single collision training session considerably increased total energy expenditure. This may explain the large energy expenditures of collision sport athletes, which appear to exceed kinematic training and match demands. These findings suggest fuelling professional collision-sport athletes appropriately for the "muscle damage caused” alongside the kinematic “work required”. Key words: Nutrition, Recovery, Contact, Rugb

In Vitro Pharmacological Characterization of RXFP3 Allosterism: An Example of Probe Dependency

Recent findings suggest that the relaxin-3 neural network may represent a new ascending arousal pathway able to modulate a range of neural circuits including those affecting circadian rhythm and sleep/wake states, spatial and emotional memory, motivation and reward, the response to stress, and feeding and metabolism. Therefore, the relaxin-3 receptor (RXFP3) is a potential therapeutic target for the treatment of various CNS diseases. Here we describe a novel selective RXFP3 receptor positive allosteric modulator (PAM), 3-[3,5-Bis(trifluoromethyl)phenyl]-1-(3,4-dichlorobenzyl)-1-[2-(5-methoxy-1H-indol-3-yl)ethyl]urea (135PAM1). Calcium mobilization and cAMP accumulation assays in cell lines expressing the cloned human RXFP3 receptor show the compound does not directly activate RXFP3 receptor but increases functional responses to amidated relaxin-3 or R3/I5, a chimera of the INSL5 A chain and the Relaxin-3 B chain. 135PAM1 increases calcium mobilization in the presence of relaxin-3NH2 and R3/I5NH2 with pEC50 values of 6.54 (6.46 to 6.64) and 6.07 (5.94 to 6.20), respectively. In the cAMP accumulation assay, 135PAM1 inhibits the CRE response to forskolin with a pIC50 of 6.12 (5.98 to 6.27) in the presence of a probe (10 nM) concentration of relaxin-3NH2. 135PAM1 does not compete for binding with the orthosteric radioligand, [125I] R3I5 (amide), in membranes prepared from cells expressing the cloned human RXFP3 receptor. 135PAM1 is selective for RXFP3 over RXFP4, which also responds to relaxin-3. However, when using the free acid (native) form of relaxin-3 or R3/I5, 135PAM1 doesn't activate RXFP3 indicating that the compound's effect is probe dependent. Thus one can exchange the entire A-chain of the probe peptide while retaining PAM activity, but the state of the probe's c-terminus is crucial to allosteric activity of the PAM. These data demonstrate the existence of an allosteric site for modulation of this GPCR as well as the subtlety of changes in probe molecules that can affect allosteric modulation of RXFP3

Selective phosphodiesterase inhibitors: a promising target for cognition enhancement

# The Author(s) 2008. This article is published with open access at Springerlink.com Rationale One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer’s disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP. Objective The aim of this review was to provide an overvie