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Sufficient high-quality studies in sport science using women as participants are lacking, meaning that our knowledge and understanding of female athletes in relation to their ovarian hormone profiles is limited. Consortia can be used to pool talent, expertise and data, thus accelerating our learning on a given topic and reducing research waste through collaboration. To this end, we have assembled an international multisite team, described here, to investigate the effects of the menstrual cycle and contraceptive pill phase on aspects of exercise physiology and sports performance in female athletes. We intend to produce an adequately powered, high-quality dataset, which can be used to inform the practices of female athletes. Our approach will also employ research transparency-through the inclusion of a process evaluation-and reproducibility-through a standardised study protocol., Competing Interests: Competing interests: KES has received funding from Arsenal Football Club, The English Institute of Sport, the European Club Association and the UK Ministry of Defence to conduct research on female athletes. None of these grants have direct competing interests with the Feminae project. KA has received funding/honoraria from the Wu Tsai Human Performance Alliance, Gatorade Sport Science Institute, Hologic, UptoDate and the US Olympic and Paralympic Committee. This funding does not have a direct competing interest with the Feminae project. CML has no competing or conflicts of interest. CM has received funding from the Australian Institute of Sport, the Queensland Academy of Sport, and an industry partner (cannot be named here) to conduct research on female athletes. None of these grants have direct competing interests with the Feminae project. CS has received funding from the UK Ministry of Defence to conduct research on female military personnel. This funding does not have direct competing interests with the Feminae project. TS has received funding/honoraria from the Wu Tsai Human Performance Alliance, Ineos, Science in Sport (Sis) Own The Podium, Gatorade Sport Science Institute and Lululemon Athletica to support research, including projects on female participants. None of these grants have a direct competing interest with the Feminae project. PAS has no competing or conflicts of interest. ACH has no competing or conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Low energy availability (LEA) is prevalent in active individuals and negatively impacts bone turnover in young females. High-impact exercise can promote bone health in an energy efficient manner and may benefit bone during periods of LEA. Nineteen regularly menstruating females (aged 18-31 years) participated in two three-day conditions providing 15 (LEA) and 45 kcals kg fat-free mass -1  day -1 (BAL) of energy availability, each beginning 3 ± 1 days following the self-reported onset of menses. Participants either did (LEA+J, n = 10) or did not (LEA, n = 9) perform 20 high-impact jumps twice per day during LEA, with P1NP, β-CTx (circulating biomarkers of bone formation and resorption, respectively) and other markers of LEA measured pre and post in a resting and fasted state. Data are presented as estimated marginal mean ± 95% CI. P1NP was significantly reduced in LEA (71.8 ± 6.1-60.4 ± 6.2 ng mL -1 , p < 0.001, d = 2.36) and LEA+J (93.9 ± 13.4-85.2 ± 12.3 ng mL -1 , p < 0.001, d = 1.66), and these effects were not significantly different (time by condition interaction: p = 0.269). β-CTx was significantly increased in LEA (0.39 ± 0.09-0.46 ± 0.10 ng mL -1 , p = 0.002, d = 1.11) but not in LEA+J (0.65 ± 0.08-0.65 ± 0.08 ng mL -1 , p > 0.999, d = 0.19), and these effects were significantly different (time by condition interaction: p = 0.007). Morning basal bone formation rate is reduced following 3 days LEA, induced via dietary restriction, with or without high-impact jumping in regularly menstruating young females. However, high-impact jumping can prevent an increase in morning basal bone resorption rate and may benefit long-term bone health in individuals repeatedly exposed to such bouts., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Bone mass and quality decline with age, and can culminate in osteoporosis and increased fracture risk. This investigation modeled associations between bone and physical, dietary, and metabolic factors in a group of 200 pre-frail/frail older adults using factor analysis and structural equation modeling (SEM). Exploratory (EFA) and confirmatory factor analysis (CFA) were conducted to compose factors and to assess their robustness. SEM was used to quantify associations between bone and the other factors. Factors arising from EFA and CFA were: bone (whole body, lumbar and femur bone mineral density, and trabecular bone score; good fit), body composition - lean (lean mass, body mass, vastus lateralis, and femoral cross-sectional area; good fit), body composition - fat (total fat mass, gynoid, android, and visceral fat; acceptable fit), strength (bench and leg press, handgrip, and knee extension peak torque; good fit), dietary intake (kilocalories, carbohydrate, protein, and fat; acceptable fit), and metabolic status (cortisol, insulin-like growth factor 1 (IGF-1), growth hormone (GH), and free testosterone; poor fit). SEM using isolated factors showed that body composition (lean) (β = 0.66, P < 0.001), body composition (fat) (β = 0.36, P < 0.001), and strength (β = 0.74, P < 0.001) positively associated with bone. Dietary intake relative to body mass negatively associated with bone (β = -0.28, P = 0.001), whereas in absolute terms, it showed no association (β = 0.01, P = 0.911). In a multivariable model, only strength (β = 0.38, P = 0.023) and body composition (lean) (β = 0.34, P = 0.045) associated with bone. Resistance training programs that focus on improving lean mass and strength in older individuals may benefit bone in this population. NEW & NOTEWORTHY We used factor analysis and structural equation modeling, which are rarely used in nutrition or exercise science, but constitute powerful tools that may overcome limitations of traditional analyses, combining individual related variables into factors or constructs of interest. Our investigation represents a starting point on this progressive pathway, providing useful insight and a working model for researchers and practitioners who wish to tackle complex problems such as the multifactorial causes of bone loss in older adults.

This large cohort study investigated reliability and validity of heel ultrasound to estimate bone mineral density in adults. Reliability calculated between left and right heels was relatively poor and so was criterion validity assessed relative to dual-energy X-ray absorptiometry. Heel ultrasound should be used cautiously when estimating bone mineral density., Introduction: Calcaneal quantitative ultrasound (QUS) may be used as a safe, low cost, and portable means to estimate bone mineral density (BMD) in large cohorts. The purpose of this study was to quantify the reliability and validity of QUS in comparison to dual-energy X-ray absorptiometry (DXA), which is the reference method for BMD measurement and diagnoses of osteopenia and osteoporosis., Methods: Bone outcomes measured on the large UK Biobank cohort were used. The reliability of QUS estimated BMD was quantified by comparing values obtained from the left and right heel measured in the same session. Criterion validity was assessed through agreement between QUS and DXA, quantifying correlations, and sensitivity and specificity of osteopenia and osteoporosis diagnoses., Results: Reliability calculations were made using data from over 216,000 participants demonstrating similar QUS BMD values between left and right heels in the absolute scale (Sd of difference for men: 0.12 and 0.07 g·cm -2 ). However, when expressed in relative scales, including concordance of quartiles, reliability was poor. Agreement between QUS and DXA was quantified using data from 5042 participants. Low to modest correlations (r = 0.29 to 0.44) were obtained between multiple QUS variables and DXA BMD, with sensitivity identified as very poor (0.05 to 0.23) for osteoporosis, and poor (0.37 to 0.62) for osteopenia diagnoses., Conclusions: The findings of this large comparative analysis identify that whilst calcaneal QUS has the potential to produce reliable absolute BMD measurements and demonstrate modest associations with DXA BMD measures, use of that information to make relative statements about participants in the context of the larger population or to appropriately diagnose osteopenia or osteoporosis may be severely limited., (© 2023. The Author(s).)

Falls and osteoporotic fractures are a major public health problem, particularly among older adults. A third of individuals aged 65 years and over fall at least once each year, with up to 20 % of these resulting in serious injury, including fracture. In conjunction with regular exercise, the importance of diet for musculoskeletal health has largely focused upon calcium, vitamin D, and protein, particularly in the context of preventing falls and fractures. Whilst there is evidence for the benefits of these nutrients for musculoskeletal health, other aspects of the diet remain largely underexplored. For example, vegetables are rich sources of macro- and micronutrients that are essential for muscle function and bone health, which are key factors in the prevention of falls and fractures. Recent work has highlighted the importance of nutrients such as vegetable-derived nitrate and vitamin K1 in optimising muscle strength, physical function, and bone quality. In the context of dietary patterns, vegan/plant-based diets have recently gained popularity due to perceived health benefits, animal welfare, or to tackle climate change. The elimination and/or substitution of animal-based products for plant foods (without careful planning and/or expert dietary guidance) could, however, have long-term negative musculoskeletal consequences; a trend uncovered by recent evidence. Within the overarching theme of nutrition for fall and fracture prevention in older populations, the aim of this review is to (i) summarise the current evidence for calcium, vitamin D and protein; (ii) describe the importance of vegetables and selected nutrients, such as nitrate and vitamin K1, for muscle function and bone structural integrity; and (iii) highlight current evidence around different dietary patterns ( e.g. , plant-based, diet quality, data driven approaches) and their impact on musculoskeletal health., Competing Interests: All authors declare no conflicts of interest specific to the completion of this article. Craig Sale has, however, received honoraria from the Dairy Council UK the Dairy Council Northern Ireland and nutritional supplement companies to speak at events on topics broadly relevant to the current article., (© 2023 The Authors.)

Introduction: There is limited information regarding the association between external load and estimated bone load in sport, which may be important due to the influence exercise can have on bone accrual and injury risk. The aim of this study was to identify external load measuring tools used by support staff to estimate bone load and assess if these methodologies were supported in research., Methods: A survey was comprised of 19 multiple choice questions and the option to elaborate on if/how they monitor external load and if/how they used them to estimate bone load. A narrative review was performed to assess how external load is associated to bone in research., Results: Participants were required to be working as support staff in applied sport. Support staff ( n  = 71) were recruited worldwide with the majority (85%) working with professional elite athletes. 92% of support staff monitored external load in their organisation, but only 28% used it to estimate bone load., Discussion: GPS is the most commonly used method to estimate bone load, but there is a lack of research assessing GPS metrics with bone load. Accelerometry and force plates were among the most prevalent methods used to assess external load, but a lack of bone specific measurements were reported by support staff. Further research exploring how external load relates to bone is needed as there is no consensus on which method of external load is best to estimate bone load in an applied setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Scott, James, Barnett, Sale and Varley.)

The ADP-ribosyltransferase, PARP1 enzymatically generates and applies the post-translational modification, ADP-Ribose (ADPR). PARP1 roles in genome maintenance are well described, but recent work highlights roles in many fundamental processes including cellular identity and energy homeostasis. Herein, we show in both mouse and human skeletal muscle cells that PARP1-mediated PARylation is a regulator of the myogenic program and the muscle transcriptional response to steroid hormones. Chemical PARP1 modulation impacts the expression of major myocellular proteins, including troponins, key in dictating muscle contractile force. Whilst PARP1 in absence of DNA damage is often assumed to be basally inactive, we show PARylation to be acutely sensitive to extracellular glucose concentrations and the steroid hormone class, glucocorticoids which exert considerable authority over muscle tissue mass. Specifically, we find during myogenesis, a transient and significant rise in PAR. This early-stage differentiation event, if blocked with PARP1 inhibition, reduced the abundance of important muscle proteins in the fully differentiated myotubes. This suggests that PAR targets during early-stage differentiation are central to the proper development of the muscle contractile unit. We also show that reduced PARP1 in myoblasts impacts a variety of metabolic pathways in line with the recorded actions of glucocorticoids. Currently, as both regulators of myogenesis and muscle mass loss, glucocorticoids represent a clinical conundrum. Our work goes on to identify that PARP1 influences transcriptional activation by glucocorticoids of a subset of genes critical to human skeletal muscle pathology. These genes may therefore signify a regulatory battery of targets through which selective glucocorticoid modulation could be achieved. Collectively, our data provide clear links between PARP1-mediated PARylation and skeletal muscle homeostatic mechanisms crucial to tissue mass maintenance and endocrine response., (© 2023. The Author(s).)

We examined the relationship between football-specific training and changes in bone structural properties across a 12-week period in 15 male football players aged 16 years (Mean ± 1 SD = 16.6 ± 0.3 years) that belonged to a professional football academy. Tibial scans were performed at 4%, 14% and 38% sites using peripheral quantitative computed tomography immediately before and 12 weeks after increased football-specific training. Training was analysed using GPS to quantify peak speed, average speed, total distance and high-speed distance. Analyses were conducted with bias-corrected and accelerated bootstrapped 95% confidence intervals (BCa 95% CI). There were increases in bone mass at the 4% (mean ∆ = 0.15 g, BCa 95% CI = 0.07, 0.26 g, g = 0.72), 14% (mean ∆ = 0.04 g, BCa 95% CI = 0.02, 0.06 g, g = 1.20), and 38% sites (mean ∆ = 0.03 g, BCa 95% CI = 0.01, 0.05 g, g = 0.61). There were increases in trabecular density (4%), (mean ∆ = 3.57 mg·cm -3 , BCa 95% CI = 0.38, 7.05 mg·cm -3 , g = 0.53), cortical dentsity (14%) (mean ∆ = 5.08 mg·cm -3 , BCa 95% CI = 0.19, 9.92 mg·cm -3 , g = 0.49), and cortical density (38%) (mean ∆ = 6.32 mg·cm -3 , BCa 95% CI = 4.31, 8.90 mg·cm -3 , g = 1.22). Polar stress strain index (mean ∆ = 50.56 mm 3 , BCa 95% CI = 10.52, 109.95 mm 3 , g = 0.41), cortical area (mean ∆ = 2.12 mm 2 , BCa 95% CI = 0.09, 4.37 mm 2 , g = 0.48) and thickness (mean ∆ = 0.06 mm, BCa 95% CI = 0.01, 0.13 mm, g = 0.45) increased at the 38% site. Correlations revealed positive relationships between total distance and increased cortical density (38%) (r = 0.39, BCa 95% CI = 0.02, 0.66), and between peak speed and increased trabecular density (4%) (r = 0.43, BCa 95% CI = 0.03, 0.73). There were negative correlations between total (r = -0.21, BCa 95% CI = -0.65, -0.12) and high-speed distance (r = -0.29, BCa 95% CI = -0.57, -0.24) with increased polar stress strain index (38%). Results suggest that despite football training relating to increases in bone characteristics in male academy footballers, the specific training variables promoting adaptation over a 12-week period may vary. Further studies conducted over a longer period are required to fully elucidate the time-course of how certain football-specific training characteristics influence bone structural properties.

Type-2 diabetes (T2D) is characterised by a dysregulation of metabolism, including skeletal muscle insulin resistance, mitochondrial dysfunction, and oxidative stress. Reactive species, such as methylglyoxal (MGO) and 4-hydroxynonenal (4-HNE), positively associate with T2D disease severity and can directly interfere with insulin signalling and glucose uptake in skeletal muscle by modifying cellular proteins. The multifunctional dipeptide carnosine, and its rate-limiting precursor β-alanine, have recently been shown to improve glycaemic control in humans and rodents with diabetes. However, the precise mechanisms are unclear and research in human skeletal muscle is limited. Herein, we present novel findings in primary human T2D and lean healthy control (LHC) skeletal muscle cells. Cells were differentiated to myotubes, and treated with 10 mM carnosine, 10 mM β-alanine, or control for 4-days. T2D cells had reduced ATP-linked and maximal respiration compared with LHC cells (p = 0.016 and p = 0.005). Treatment with 10 mM carnosine significantly increased insulin-stimulated glucose uptake in T2D cells (p = 0.047); with no effect in LHC cells. Insulin-stimulation increased MGO-modified proteins in T2D cells by 47%; treatment with carnosine attenuated this increase to 9.7% (p = 0.011). There was no effect treatment on cell viability or expression of other proteins. These findings suggest that the beneficial effects of carnosine on glycaemic control may be explained by its scavenging actions in human skeletal muscle., (© 2023. The Author(s).)

Background: There is an unmet need for an accurate, validated, noninvasive test for diagnosing and monitoring bladder cancer (BC). Detection of BC-associated mutations in urinary DNA via targeted deep sequencing could meet this need., Objective: To test the ability of mutational analysis of urinary DNA to noninvasively detect BC within the context of haematuria investigations and non-muscle-invasive BC (NMIBC) surveillance., Design, Setting, and Participants: Capture-based ultra-deep sequencing was performed for 443 somatic mutations in 23 genes in 591 urine cell-pellet DNAs from haematuria clinic patients and 293 from NMIBC surveillance patients. Variant calling was optimised to minimise false positives using urine samples from 162 haematuria clinic patients without BC., Outcome Measurements and Statistical Analysis: The sensitivity and specificity for BC diagnosis were determined., Results and Limitations: Mutational analysis of urinary DNA detected 144 of the 165 haematuria patients diagnosed with incident BC from two independent cohorts, yielding overall sensitivity of 87.3% (95% confidence interval [CI] 81.2-92.0%) at specificity of 84.8% (95% CI 79.9-89.0%). The sensitivity was 97.4% for grade 3, 86.5% for grade 2, and 70.8% for grade 1 BC. Among NMIBC surveillance patients, 25 out of 29 recurrent BCs were detected, yielding sensitivity of 86.2% (95% CI 70.8-97.7%) at specificity of 62.5% (95% CI 56.1-68.0%); a positive urine mutation test in the absence of clinically detectable disease was associated with a 2.6-fold increase in the risk of future recurrence. The low number of recurrences in the NMIBC surveillance cohort and the lower sensitivity for detecting grade 1 pTa BC are limitations., Conclusions: Detection of mutations in a small panel of BC-associated genes could facilitate noninvasive BC testing and expedite haematuria investigations. Following further validation, the test could also play a role in NMIBC surveillance., Patient Summary: Identification of alterations in genes that are frequently mutated in bladder cancer appears to be a promising strategy for detecting disease from urine samples and reducing reliance on examination of the bladder via a telescopic camera inserted through the urethra., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

This study examined the relationship between training load and changes in body composition and bone characteristics across a competitive season. Twenty senior male professional football players participated in this prospective longitudinal study. Participants underwent dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) scans on four occasions across the study period, resulting in three phases of the season. Phase 1 (Scan 1-Scan 2: 6-weeks: pre-season), Phase 2 (Scan 2-Scan 3: 24-weeks: first part of the season), and Phase 3 (Scan 3-Scan 4: 13-weeks: second part of the season). External training load was quantified using GPS devices. In Phase 1 there was a significant increase (mean ± SE) in lean mass (from 66.0 ± 1.4 to 67.8 ± 1.4 kg) and a significant decrease in fat mass (from 11.5 ± 0.6 to 10.4 ± 0.6 kg). In Phase 2 there were significant increases in whole-body BMD (from 1.41 ± 0.02 to 1.43 ± 0.02 g/cm 2 ), leg (from 1563 ± 43 to 1572 ± 43 g) and whole-body BMC (from 3807 ± 100 to 3860 ± 100 g), tibial mass (14 % site) (from 3.72 ± 0.08 to 3.74 ± 0.08 g), tibial strength (SSI(POL)14 % site) (from 2331 ± 78 to 2378 ± 78 mm 3 ), and tibial density (4 % site) (from 382 ± 8 to 388 ± 8 mm 3 ). In Phase 3, there was a significant decrease in tibial mass (14 % site) (from 3.74 ± 0.08 to 3.72 ± 0.08 g). Bootstrapped (BCa 95 % CI) Pearson correlations showed that in Phase 2 there were significant positive relationships between the increases in leg BMC and total distance (r = 0.44, 0.01-0.80), accelerations (r = 0.45, 0.08-0.75), and decelerations (r = 0.49, 0.07-0.83), and between the increase in tibial strength (SSI(POL)14 % site) and accelerations (r = 0.53, 0.19-0.80). High magnitude dynamic actions, such as accelerations and decelerations were positively correlated with changes in bone characteristics during a professional football season and should be considered by practitioners when prescribing exercise to induce bone adaptation., Competing Interests: None., (Crown Copyright © 2022 Published by Elsevier Inc.)

Purpose: This study aimed to determine vitamin D metabolites and vitamin D receptor (VDR) single-nucleotide polymorphism (SNP) relationships with physical performance., Methods: In 1205 men and 322 women (94.8% White Caucasian, 22.0 ± 2.8 yr) commencing military training, we measured serum vitamin D metabolites (25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH) 2 D) by high-performance liquid chromatography tandem mass spectrophotometry and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) by immunoassay), VDR SNPs (rs2228570, rs4516035, and rs7139166 by polymerase chain reaction genotyping), and endurance performance by 2.4-km run, muscle strength by maximal dynamic lift, and muscle power by maximal vertical jump., Results: Serum 25(OH)D was negatively associated with 2.4-km run time and positively associated with muscle power ( β = -12.0 and 90.1), 1,25(OH) 2 D was positively associated with run time and negatively associated with strength and muscle power ( β = 5.6, -1.06, and -38.4), and 24,25(OH) 2 D was negatively associated with run time ( β = -8.9; P < 0.01), after controlling for age, sex, smoking, alcohol, physical activity, time outdoors, season, and body mass index. Vitamin D metabolites (25(OH)D, 1,25(OH) 2 D, and 24,25(OH) 2 D) together explained variances of 5.0% in run time, 0.7% in strength, and 0.9% in muscle power (Δ F P < 0.001). All performance measures were superior with low 1,25(OH) 2 D:24,25(OH) 2 D ratio ( P < 0.05). VDR SNPs were not associated with physical performance (Δ FP ≥ 0.306)., Conclusions: Vitamin D metabolites accounted for a small portion of variance in physical performance. Associations between vitamin D metabolites and run time were the most consistent. VDR SNPs explained no variance in performance. Greater conversion of 25(OH)D to 24,25(OH) 2 D, relative to 1,25(OH) 2 D (i.e., low 1,25(OH) 2 D:24,25(OH) 2 D ratio), was favorable for performance, indicating 24,25(OH) 2 D may have a role in optimizing physical performance., (Copyright © 2022 by the American College of Sports Medicine.)

Carnosine is a pleiotropic histidine-containing dipeptide synthesized from β-alanine and l-histidine, with the intact dipeptide and constituent amino acids being available from the diet. The therapeutic application of carnosine in myocardial tissue is promising, with carnosine playing a potentially beneficial role in both healthy and diseased myocardial models. This narrative review discusses the role of carnosine in myocardial function and health, including an overview of the metabolic pathway of carnosine in the myocardial tissue, the roles carnosine may play in the myocardium, and a critical analysis of the literature, focusing on the effect of exogenous carnosine and its precursors on myocardial function. By so doing, we aim to identify current gaps in the literature, thereby identifying considerations for future research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Acute morning fasted exercise may create a greater negative 24-hr energy balance than the same exercise performed after a meal, but research exploring fasted evening exercise is limited. This study assessed the effects of 7-hr fasting before evening exercise on energy intake, metabolism, and performance. Sixteen healthy males and females (n = 8 each) completed two randomized, counterbalanced trials. Participants consumed a standardized breakfast (08:30) and lunch (11:30). Two hours before exercise (16:30), participants consumed a meal (543 ± 86 kcal; FED) or remained fasted (FAST). Exercise involved 30-min cycling (∼60% VO2peak) and a 15-min performance test (∼85% VO2peak; 18:30). Ad libitum energy intake was assessed 15 min postexercise. Subjective appetite was measured throughout. Energy intake was 99 ± 162 kcal greater postexercise (p < .05), but 443 ± 128 kcal lower over the day (p < .001) in FAST. Appetite was elevated between the preexercise meal and ad libitum meal in FAST (p < .001), with no further differences (p ≥ .458). Fat oxidation was greater (+3.25 ± 1.99 g), and carbohydrate oxidation was lower (-9.16 ± 5.80 g) during exercise in FAST (p < .001). Exercise performance was 3.8% lower in FAST (153 ± 57 kJ vs. 159 ± 58 kJ, p < .05), with preexercise motivation, energy, readiness, and postexercise enjoyment also lower in FAST (p < .01). Fasted evening exercise reduced net energy intake and increased fat oxidation compared to exercise performed 2 hr after a meal. However, fasting also reduced voluntary performance, motivation, and exercise enjoyment. Future studies are needed to examine the long-term effects of this intervention as a weight management strategy.

This study investigated the effect of beta-alanine supplementation on short-duration sprints and final 4-km simulated uphill cycling time-trial performance during a comprehensive and novel exercise protocol representative of the demands of road-race cycling, and determined if changes were related to increases in muscle carnosine content. Seventeen cyclists (age 38 ± 9 y, height 1.76 ± 0.07 m, body mass 71.4 ± 8.8 kg, V̇O 2max  52.4 ± 8.3 ml·kg -1 ·min -1 ) participated in this placebo-controlled, double-blind study. Cyclists undertook a prolonged intermittent cycling protocol lasting 125 min, with a 10-s sprint every 20 min, finishing with a 4-km time-trial at 5% simulated incline. Participants completed two familiarization sessions, and two main sessions, one pre-supplementation and one post-supplementation following 28 days of 6.4 g·day -1 of beta-alanine (N=11) or placebo (N=6; maltodextrin). Muscle biopsies obtained pre- and post-supplementation were analysed for muscle carnosine content. There were no main effects on sprint performance throughout the intermittent cycling test (all P >0.05). There was no group ( P =0.69), time ( P =0.50) or group x time interaction ( P =0.26) on time-to-complete the 4-km time-trial. Time-to-completion did not change from pre- to post-supplementation for BA (-19.2 ± 45.6 s, P =0.43) or PL (+2.8 ± 31.6 s, P =0.99). Beta-alanine supplementation increased muscle carnosine content from pre- to post-supplementation (+9.4 ± 4.0 mmol·kg -1 dm; P <0.0001) but was not related to performance changes (r=0.320, P =0.37). Chronic beta-alanine supplementation increased muscle carnosine content but did not improve short-duration sprint performance throughout simulated road race cycling, nor 4-km uphill time-trial performance conducted at the end of this cycling test. Highlights Performance during prolonged cycling events often depends on the ability to maintain an increased power output during higher intensity periods. Thus, cyclists are likely heavily dependent on their ability to resist fatigue during these periods of high-intensity activity.Meta-analytical data show beta-alanine to be an effective supplement to improve exercise outcomes, but little work exists on its efficacy during dynamic actions that are common during prolonged cycling.Beta-alanine supplementation increased muscle carnosine content but did not generate improvements in the performance of high-intensity cycling (10-s sprints or 4-km uphill time-trial) during a simulated road race cycling protocol.These data suggest that short duration sprints (≤10 s) and longer duration (>10 min) high-intensity activity throughout endurance cycling may not be improved with beta-alanine supplementation despite increases in muscle carnosine content.

This study examined potential fluctuations in bone metabolic markers across the menstrual cycle both at rest and after a 30-min bout of continuous running at 80% of V̇O 2max . Resting and post-exercise (0, 30, 90 min) sclerostin, parathyroid hormone (PTH), carboxy-terminal cross-linking telopeptide of type I collagen (β-CTXI), and procollagen type 1 N propeptide (PINP) were assessed in 10 eumenorrheic women (age: 21 ± 3 y, BMI: 23.2 ± 3.0 kg . m 2 ) during the mid- to late-follicular (FP: day 8.0 ± 1.4) and mid-luteal (LP: day 22.0 ± 2.5) phases of the menstrual cycle. Ovulation was determined using ovulation kits and daily measurement of oral body temperature upon awakening. Menstrual cycle phase was subsequently confirmed by measurement of plasma estradiol and progesterone. On average, resting estradiol concentrations increased from 46.3 ± 8.9 pg·mL -1 in the FP to 67.3 ± 23.4 pg·mL -1 in the LP (p = 0.015), and resting progesterone increased from 4.12 ± 2.36 ng·mL -1 in the FP to 11.86 ± 4.49 ng·mL -1 in the LP (p < 0.001). At rest, there were no differences between menstrual cycle phases in sclerostin (FP: 260.1 ± 135.0 pg·mL -1 ; LP: 303.5 ± 99.9 pg·mL -1 ; p = 0.765), PTH (FP: 0.96 ± 0.64 pmol·L -1 ; LP: 0.79 ± 0.44 pmol·L -1 ; p = 0.568), β-CTXI (FP: 243.1 ± 158.0 ng·L -1 ; LP: 202.4 ± 92.3 ng·L -1 ; p = 0.198), and PINP (FP: 53.6 ± 8.9 μg·L -1 ; LP: 66.2 ± 20.2 μg·L -1 ; p = 0.093). Main effects for time (p < 0.05) were shown in sclerostin, PTH, β-CTXI and PINP, without phase or interaction effects. Sclerostin increased from pre- to immediately post-exercise (45%; p = 0.007), and so did PTH (43%; p = 0.011), both returning to resting concentrations 30 min post-exercise. β-CTXI decreased from pre- to post-exercise (20%; p = 0.027) and was still below its pre-exercise concentrations at 90 min post-exercise (17%; p = 0.013). PINP increased immediately post-exercise (29%; p < 0.001), returning to resting concentrations at 30 min post-exercise. These results demonstrate no effect of menstrual cycle phase on resting bone marker concentrations or on the bone metabolic marker response to intense exercise., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Postpartum women are at an increased risk of pelvic floor dysfunction, musculoskeletal injury, and poor psychological health and have reduced physical fitness compared to before pregnancy. There is no formal, evidence-based rehabilitation and physical development program for returning UK servicewomen to work following childbirth., Objective: This study aims to examine the efficacy of a rehabilitation and physical development intervention for returning postpartum UK servicewomen to occupational fitness., Methods: Eligible servicewomen will be assigned to a training or control group in a nonrandomized controlled trial 6 weeks after childbirth. Group allocation will be based on the location of standard pregnancy and postpartum care. The control group will receive standard care, with no prescribed intervention. The training group will start an 18-week core and pelvic health rehabilitation program 6 weeks post partum and a 12-week resistance and high-intensity interval training program 12 weeks post partum. All participants will attend 4 testing sessions at 6, 12, 18, and 24 weeks post partum for the assessment of occupational physical performance, pelvic health, psychological well-being, quality of life, and musculoskeletal health outcomes. Occupational physical performance tests will include vertical jump, mid-thigh pull, seated medicine ball throw, and a timed 2-km run. Pelvic health tests will include the Pelvic Organ Prolapse Quantification system, the PERFECT (power, endurance, repetitions, fast, every contraction timed) scheme for pelvic floor strength, musculoskeletal physiotherapy assessment, the Pelvic Floor Distress Inventory-20 questionnaire, and the International Consultation on Incontinence Questionnaire-Vaginal Symptoms. Psychological well-being and quality of life tests will include the World Health Organization Quality of Life questionnaire and the Edinburgh Postnatal Depression Scale. Musculoskeletal health outcomes will include body composition; whole-body areal bone mineral density; tibial volumetric bone mineral density, geometry, and microarchitecture; patella tendon properties; muscle architecture; muscle protein and collagen turnover; and muscle mass and muscle breakdown. Data will be analyzed using linear mixed-effects models, with participants included as random effects, and group and time as fixed effects to assess within- and between-group differences over time., Results: This study received ethical approval in April 2019 and recruitment started in July 2019. The study was paused in March 2020 owing to the COVID-19 pandemic. Recruitment restarted in May 2021. The results are expected in September 2022., Conclusions: This study will inform the best practice for the safe and optimal return of postpartum servicewomen to physically and mentally demanding jobs., Trial Registration: ClinicalTrials.gov NCT04332757; https://clinicaltrials.gov/ct2/show/NCT04332757., International Registered Report Identifier (irrid): DERR1-10.2196/32315., (©Kirsty Jayne Elliott-Sale, Emma Louise Bostock, Thea Jackson, Sophie Louise Wardle, Thomas James O'Leary, Julie Patricia Greeves, Craig Sale. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 01.06.2022.)

The energy costs of athletic training can be substantial, and deficits arising from costs unmet by adequate energy intake, leading to a state of low energy availability, may adversely impact athlete health and performance. Life history theory is a branch of evolutionary theory that recognizes that the way the body uses energy-and responds to low energy availability-is an evolved trait. Energy is a finite resource that must be distributed throughout the body to simultaneously fuel all biological processes. When energy availability is low, insufficient energy may be available to equally support all processes. As energy used for one function cannot be used for others, energetic "trade-offs" will arise. Biological processes offering the greatest immediate survival value will be protected, even if this results in energy being diverted away from others, potentially leading to their downregulation. Athletes with low energy availability provide a useful model for anthropologists investigating the biological trade-offs that occur when energy is scarce, while the broader conceptual framework provided by life history theory may be useful to sport and exercise researchers who investigate the influence of low energy availability on athlete health and performance. The goals of this review are: (1) to describe the core tenets of life history theory; (2) consider trade-offs that might occur in athletes with low energy availability in the context of four broad biological areas: reproduction, somatic maintenance, growth, and immunity; and (3) use this evolutionary perspective to consider potential directions for future research., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: This study aimed to assess the effects of consuming a very-low-energy placebo breakfast on subsequent appetite and lunch energy intake., Methods: Fourteen healthy males consumed water-only (WAT), very-low-energy, viscous placebo (containing water, low-calorie flavoured squash, and xanthan gum; ~ 16 kcal; PLA), and whole-food (~ 573 kcal; FOOD) breakfasts in a randomised order. Subjects were blinded to the energy content of PLA and specific study aims. Venous blood samples were collected pre-breakfast, 60- and 180-min post-breakfast to assess plasma acylated ghrelin and peptide tyrosine tyrosine concentrations. Subjective appetite was measured regularly, and energy intake was assessed at an ad libitum lunch meal 195-min post-breakfast., Results: Lunch energy intake was lower during FOOD compared to WAT (P < 0.05), with no further differences between trials (P ≥ 0.132). Cumulative energy intake (breakfast plus lunch) was lower during PLA (1078 ± 274 kcal) and WAT (1093 ± 249 kcal), compared to FOOD (1554 ± 301 kcal; P < 0.001). Total area under the curve (AUC) for hunger, desire to eat and prospective food consumption were lower, and fullness was greater during PLA and FOOD compared to WAT (P < 0.05). AUC for hunger was lower during FOOD compared to PLA (P < 0.05). During FOOD, acylated ghrelin was suppressed compared to PLA and WAT at 60 min (P < 0.05), with no other hormonal differences between trials (P ≥ 0.071)., Conclusion: Consuming a very-low-energy placebo breakfast does not alter energy intake at lunch but may reduce cumulative energy intake across breakfast and lunch and attenuate elevations in subjective appetite associated with breakfast omission., Trial Registration: NCT04735783, 2nd February 2021, retrospectively registered., (© 2021. The Author(s).)

Background: Given the increased occurrence of pre-gravid obesity in recent years, and the implications of maternal obesity for maternal and offspring health, it is evident that there is a continued need to investigate antenatal and postnatal weight management strategies and to provide evidence-based advice for exercise-based interventions. Given the small number of studies ( n  = 5) included in an original systematic review by our group in 2015, it was important to add to the dataset by assessing data published since 2015, in order to provide a more in-depth view of current knowledge., Objective: To provide an updated systematic review on studies employing exercise interventions for weight management in pregnant and postpartum women., Methods: A systematic review of randomised controlled trials evaluating the effects of an exercise intervention on gestational weight gain and postpartum weight management in normal weight women, and women with overweight and obesity was conducted. PubMed, Scopus, Central Register of Controlled Trials and Web of Science were searched for studies published between September 2013 and June 2021. No restrictions were set on type, intensity, duration, or frequency of exercise intervention. Only studies that targeted body weight or mass as a primary outcome were included., Results: Thirteen studies were included in this review: 11 during and two following pregnancy. Exercise significantly reduced gestational weight gain in five of the pregnancy studies and induced significant weight loss in one of the postpartum studies. Across studies, there were large disparities in exercise modality, frequency, and duration, although moderate intensity exercise was consistently employed., Conclusions: Some studies showed positive effects of exercise on weight management during and following pregnancy. While there is still no consensus on effective exercise intervention approaches, it is crucial that physical activity, of any safe form, is recommended to encourage healthy weight management during this time., Competing Interests: The authors declared no conflict of interest., (© 2022 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Best-practice guidance and management of pregnant and postpartum elite athletes and women in arduous occupations is limited by the lack of high-quality evidence available within these populations. We have summarized the adaptations and implications of pregnancy and childbirth, proposed a novel integrative concept to address these changes, and made recommendations to progress research in this area., (Copyright © 2021 by the American College of Sports Medicine.)

Freshwater turtles found in higher latitudes can experience extreme challenges to acid-base homeostasis while overwintering, due to a combination of cold temperatures along with the potential for environmental hypoxia. Histidine-containing dipeptides (HCDs; carnosine, anserine and balenine) may facilitate pH regulation in response to these challenges, through their role as pH buffers. We measured the HCD content of three tissues (liver, cardiac and skeletal muscle) from the anoxia-tolerant painted turtle (C. picta bellii) acclimated to either 3 or 20 °C. HCDs were detected in all tissues, with the highest content shown in the skeletal muscle. Turtles acclimated to 3 °C had more HCD in their skeletal muscle than those acclimated to 20 °C (carnosine = 20.8 ± 4.5 vs 12.5 ± 5.9 mmol·kg DM -1 ; ES = 1.59 (95%CI: 0.16-3.00), P = 0.013). The higher HCD content shown in the skeletal muscle of the cold-acclimated turtles suggests a role in acid-base regulation in response to physiological challenges associated with living in the cold, with the increase possibly related to the temperature sensitivity of carnosine's dissociation constant., (Copyright © 2021. Published by Elsevier Inc.)

There is growing evidence that supplementation with carnosine, or its rate-limiting precursor β-alanine, can ameliorate aspects of metabolic dysregulation that occur in diabetes and its related conditions. The purpose of this systematic review and meta-analysis was to evaluate the effect of carnosine or β-alanine supplementation on markers of glycemic control and insulin resistance in humans and animals. We performed a systematic search of 6 electronic databases up to 31 December 2020. Primary outcomes were changes in 1) fasting glucose, 2) glycated hemoglobin (HbA1c), and 3) 2-h glucose following a glucose-tolerance test. A set of additional outcomes included fasting insulin and homeostatic model assessment of β-cell function (HOMA-β) and insulin resistance (HOMA-IR). We assessed risk of bias using the Cochrane risk of bias (RoB) 2.0 (human studies) and the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) RoB (animal studies) tools; and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess certainty. We used Bayesian hierarchical random-effects models, with informative priors for human data and noninformative priors for animal data. Inferences were made on posterior samples generated by Hamiltonian Markov Chain Monte Carlo using 90% credible intervals (90% CrI) and calculated probabilities. Twenty studies (n = 4 human, n = 16 rodent) were included, providing data for 2 primary outcomes (fasting glucose and HbA1c) and 3 additional outcomes (fasting insulin, HOMA-β, and HOMA-IR). The model provides evidence that supplementation decreases fasting glucose [humans: mean difference (MD)0.5 = -0.95 mmol · L-1 (90% CrI: -2.1, 0.08); rodent: MD0.5 = -2.26 mmol · L-1 (90% CrI: -4.03, -0.44)], HbA1c [humans: MD0.5 = -0.91% (90% CrI: -1.46, -0.39); rodents: MD0.5 = -1.05% (90% CrI: -1.64, -0.52)], HOMA-IR [humans: standardized mean difference (SMD)0.5 = -0.41 (90% CrI: -0.82, -0.07); rodents: SMD0.5 = -0.63 (90% CrI: -1.98, 0.65)], and fasting insulin [humans: SMD0.5 = -0.41 (90% CrI: -0.77, -0.07)]. GRADE assessment showed our certainty in the effect estimate of each outcome to be moderate (human outcomes) or very low (rodent outcomes). Supplementation with carnosine or β-alanine may reduce fasting glucose, HbA1c, and HOMA-IR in humans and rodents, and fasting insulin in humans; both compounds show potential as therapeutics to improve glycemic control and insulin resistance. This review was registered at PROSPERO as CRD42020191588., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Type 2 diabetes is characterised by failure to control glucose homeostasis, with numerous diabetic complications attributable to the resulting exposure of cells and tissues to chronic elevated concentrations of glucose and fatty acids. This, in part, results from formation of advanced glycation and advanced lipidation end-products that are able to modify protein, lipid, or DNA structure, and disrupt normal cellular function. Herein we used mass spectrometry to identify proteins modified by two such adduction events in serum of individuals with obesity, type 2 diabetes, and gestational diabetes, along with similar analyses of human and mouse skeletal muscle cells and mouse pancreatic islets exposed to glucolipotoxic stress. We also report that carnosine, a histidine containing dipeptide, prevented 65-90% of 4-hydroxynonenal and 3-nitrotyrosine adduction events, and that this in turn preserved mitochondrial function and protected stimulus-secretion coupling in cells exposed to metabolic stress. Carnosine therefore offers significant therapeutic potential against metabolic diseases., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We evaluated whether insulin could stimulate β-alanine uptake by skeletal muscle cells in vitro. Mouse myoblasts (C2C12) (n = 3 wells per condition) were cultured with β-alanine (350 or 700 µmol·L -1 ), with insulin (100 µU·mL -1 ) either added to the media or not. Insulin stimulated the β-alanine uptake at the lower (350 µmol·L -1 ) but not higher (700 µmol·L -1 ) β-alanine concentration in culture medium, indicating that transporter saturation might blunt the stimulatory effects of insulin., (© 2021. The Author(s).)

This study determined the influence of a high- (HI) versus low-intensity (LI) cycling warm-up on blood acid-base responses and exercise capacity following ingestion of sodium bicarbonate (SB; 0.3 g/kg body mass) or a placebo (PLA; maltodextrin) 3 hr prior to warm-up. Twelve men (21 ± 2 years, 79.2 ± 3.6 kg body mass, and maximum power output [Wmax] 318 ± 36 W) completed a familiarization and four double-blind trials in a counterbalanced order: HI warm-up with SB, HI warm-up with PLA, LI warm-up with SB, and LI warm-up with PLA. LI warm-up was 15 min at 60% Wmax, while the HI warm-up (typical of elites) featured LI followed by 2 × 30 s (3-min break) at Wmax, finishing 30 min prior to a cycling capacity test at 110% Wmax. Blood bicarbonate and lactate were measured throughout. SB supplementation increased blood bicarbonate (+6.4 mmol/L; 95% confidence interval, CI [5.7, 7.1]) prior to greater reductions with HI warm-up (-3.8 mmol/L; 95% CI [-5.8, -1.8]). However, during the 30-min recovery, blood bicarbonate rebounded and increased in all conditions, with concentrations ∼5.3 mmol/L greater with SB supplementation (p < .001). Blood bicarbonate significantly declined during the cycling capacity test at 110%Wmax with greater reductions following SB supplementation (-2.4 mmol/L; 95% CI [-3.8, -0.90]). Aligned with these results, SB supplementation increased total work done during the cycling capacity test at 110% Wmax (+8.5 kJ; 95% CI [3.6, 13.4], ∼19% increase) with no significant main effect of warm-up intensity (+0.0 kJ; 95% CI [-5.0, 5.0]). Collectively, the results demonstrate that SB supplementation can improve HI cycling capacity irrespective of prior warm-up intensity, likely due to blood alkalosis.

Carnosine is a naturally occurring dipeptide found in meat. Alternatively it can be formed through synthesis from the amino acids, β-alanine and L-histidine. Carnosine has long been advocated for use as an anti-oxidant and anti-glycating agent to facilitate healthy ageing, and there have also been reports of it having anti-proliferative effects that have beneficial actions against the development of a number of different cancers. Carnosine is able to undertake multiple molecular processes, and it's mechanism of action therefore remains controversial - both in healthy tissues and those associated with cancer or metabolic diseases. Here we review current understanding of its mechanistic role in different physiological contexts, and how this relates to cancer. Carnosine turns over rapidly in the body due to the presence of both serum and tissue carnosinase enzymes however, so its use as a dietary supplement would require ingestion of multiple daily doses. Strategies are therefore being developed that are based upon either resistance of carnosine analogs to enzymatic turnover, or else β-alanine supplementation, and the development of these potential therapeutic agents is discussed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H + buffering, regulation of Ca 2+ transients and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1 -/- ) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca 2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1 -/- resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1 -/- resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca 2+ peaks and slowed Ca 2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca 2+ handling and excitation-contraction coupling., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Currently, little is known about the extent of interindividual variability in response to beta-alanine (BA) supplementation, nor what proportion of said variability can be attributed to external factors or to the intervention itself (intervention response). To investigate this, individual participant data on the effect of BA supplementation on a high-intensity cycling capacity test (CCT110%) were meta-analyzed. Changes in time to exhaustion (TTE) and muscle carnosine were the primary and secondary outcomes. Multilevel distributional Bayesian models were used to estimate the mean and SD of BA and placebo group change scores. The relative sizes of group SDs were used to infer whether observed variation in change scores were due to intervention or non-intervention-related effects. Six eligible studies were identified, and individual data were obtained from four of these. Analyses showed a group effect of BA supplementation on TTE (7.7, 95% credible interval [CrI] [1.3, 14.3] s) and muscle carnosine (18.1, 95% CrI [14.5, 21.9] mmol/kg DM). A large intervention response variation was identified for muscle carnosine (σIR = 5.8, 95% CrI [4.2, 7.4] mmol/kg DM) while equivalent change score SDs were shown for TTE in both the placebo (16.1, 95% CrI [13.0, 21.3] s) and BA (15.9, 95% CrI [13.0, 20.0] s) conditions, with the probability that SD was greater in placebo being 0.64. In conclusion, the similarity in observed change score SDs between groups for TTE indicates the source of variation is common to both groups, and therefore unrelated to the supplement itself, likely originating instead from external factors such as nutritional intake, sleep patterns, or training status.

To examine the role of chronic (in)activity on muscle carnosine (MCarn) and how chronic (in)activity affects MCarn responses to β-alanine supplementation in spinal cord-injured athletes, 16 male athletes with paraplegia were randomized (2:1 ratio) to receive β-alanine ( n = 11) or placebo (PL, n = 5). They consumed 6.4 g/day of β-alanine or PL for 28 days. Muscle biopsies of the active deltoid and the inactive vastus lateralis (VL) were taken before and after supplementation. MCarn in the VL was also compared with the VL of a group of individuals without paraplegia ( n = 15). MCarn was quantified in whole muscle and in pools of individual fibers by high-performance liquid chromatography. MCarn was higher in chronically inactive VL vs. well-trained deltoid (32.0 ± 12.0 vs. 20.5 ± 6.1 mmol/kg DM; P = 0.018). MCarn was higher in inactive vs. active VL (32.0 ± 12.0 vs. 21.2 ± 7.5 mmol/kg DM; P = 0.011). In type-I fibers, MCarn was significantly higher in the inactive VL than in the active deltoid (38.3 ± 4.7 vs. 27.3 ± 11.8 mmol/kg DM, P = 0.014). MCarn increased similarly between inactive VL and active deltoid in the β-alanine group (VL: 68.9 ± 55.1%, P = 0.0002; deltoid: 90.5 ± 51.4%, P < 0.0001), with no changes in the PL group. MCarn content was higher in the inactive VL than in the active deltoid and the active VL, but this is probably a consequence of fiber type shift (type I to type II) that occurs with chronic inactivity. Chronically inactive muscle showed an increase in MCarn after BA supplementation equally to the active muscle, suggesting that carnosine accretion following β-alanine supplementation is not influenced by muscle inactivity.

The availability of dietary beta-alanine (BA) is the limiting factor in carnosine synthesis within human muscle due to its low intramuscular concentration and substrate affinity. Carnosine can accept hydrogen ions (H + ), making it an important intramuscular buffer against exercise-induced acidosis. Metabolite accumulation rate increases when exercising in hypoxic conditions, thus an increased carnosine concentration could attenuate H + build-up when exercising in hypoxic conditions. This study examined the effects of BA supplementation on high intensity cycling capacity in normoxia and hypoxia. In a double-blind design, nineteen males were matched into a BA group (n = 10; 6.4 g·d -1 ) or a placebo group (PLA; n = 9) and supplemented for 28 days, carrying out two pre- and two post-supplementation cycling capacity trials at 110% of powermax, one in normoxia and one in hypoxia (15.5% O 2 ). Hypoxia led to a 9.1% reduction in exercise capacity, but BA supplementation had no significant effect on exercise capacity in normoxia or hypoxia ( P > 0.05). Blood lactate accumulation showed a significant trial x time interaction post-supplementation ( P = 0.016), although this was not significantly different between groups. BA supplementation did not increase high intensity cycling capacity in normoxia, nor did it improve cycling capacity in hypoxia even though exercise capacity was reduced under hypoxic conditions.

Objective: Disuse atrophy (DA) describes inactivity-induced skeletal muscle loss, through incompletely defined mechanisms. An intriguing observation is that individual muscles exhibit differing degrees of atrophy, despite exhibiting similar anatomical function/locations. We aimed to develop an innovative experimental paradigm to investigate Atrophy Resistant tibialis anterior (TA) and Atrophy Susceptible medial gastrocnemius (MG) muscles (aRaS) with a future view of uncovering central mechanisms., Method: Seven healthy young men (22 ± 1 year) underwent 15 days unilateral leg immobilisation (ULI). Participants had a single leg immobilised using a knee brace and air-boot to fix the leg (75° knee flexion) and ankle in place. Dual-energy X-ray absorptiometry (DXA), MRI and ultrasound scans of the lower leg were taken before and after the immobilisation period to determine changes in muscle mass. Techniques were developed for conchotome and microneedle TA/MG muscle biopsies following immobilisation (both limbs), and preliminary fibre typing analyses was conducted., Results: TA/MG muscles displayed comparable fibre type distribution of predominantly type I fibres (TA 67 ± 7%, MG 63 ± 5%). Following 15 days immobilisation, MG muscle volume (-2.8 ± 1.4%, p < 0.05) and muscle thickness decreased (-12.9 ± 1.6%, p < 0.01), with a positive correlation between changes in muscle volume and thickness (R 2 = 0.31, p = 0.038). Importantly, both TA muscle volume and thickness remained unchanged., Conclusion: The use of this unique "aRaS" paradigm provides an effective and convenient means by which to study the mechanistic basis of divergent DA susceptibility in humans, which may facilitate new mechanistic insights, and by extension, mitigation of skeletal muscle atrophy during human DA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bass, Hardy, Inns, Wilkinson, Piasecki, Morris, Spicer, Sale, Smith, Atherton and Phillips.)

The development of safe and practical strategies to prevent weakening of bone tissue is vital, yet attempts to achieve this have been hindered by a lack of understanding of the short-term (days-weeks) physiology of bone collagen turnover. To address this, we have developed a method to quantify bone collagen synthesis in vivo, using deuterium oxide (D 2 O) tracer incorporation techniques combined with gas chromatography pyrolysis isotope-ratio mass spectrometry (GC-pyrolysis-IRMS). Forty-six male and female rats from a selectively bred model ingested D 2 O for 3 weeks. Femur diaphyses (FEM), tibia proximal (T-PRO), and distal (T-DIS) epiphyses-metaphyses and tibia mid-shaft diaphyses (T-MID) were obtained from all rats after necropsy. After demineralisation, collagen proteins were isolated and hydrolysed and collagen fractional synthetic rates (FSRs) determined by incorporation of deuterium into protein-bound alanine via GC-pyrolysis-IRMS. The collagen FSR for the FEM (0.131 ± 0.078%/day; 95% CI [0.106-0.156]) was greater than the FSR at T-MID (0.055 ± 0.049%/day; 95% CI [0.040-0.070]; p < 0.001). The T-PRO site had the highest FSR (0.203 ± 0.123%/day; 95% CI [0.166-0.241]) and T-DIS the lowest (0.027 ± 0.015%/day; 95% CI [0.022-0.031]). The three tibial sites exhibited different FSRs (p < 0.001). Herein, we have developed a sensitive method to quantify in vivo bone collagen synthesis and identified site-specific rates of synthesis, which could be applicable to studies of human bone collagen turnover., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Purpose: This study aimed to describe the kinetics of carnosine washout in human skeletal muscle over 16 wk., Methods: Carnosine washout kinetics were studied in 15 young, physically active omnivorous men randomly assigned to take 6.4 g·d-1 of β-alanine (n = 11) or placebo (n = 4) for 8 wk. Muscle carnosine content (M-Carn) was determined before (PRE), immediately after (POST), and 4, 8, 12, and 16 wk after supplementation. High-intensity exercise tests were performed at these same time points. Linear and exponential models were fitted to the washout data, and the leave-one-out method was used to select the model with the best fit for M-Carn decay data. Repeated-measures correlation analysis was used to assess the association between changes in M-Carn and changes in performance., Results: M-Carn increased from PRE to POST in the β-alanine group only (+91.1% ± 29.1%; placebo, +0.04% ± 10.1%; P < 0.0001). M-Carn started to decrease after cessation of β-alanine supplementation and continued to decrease until week 16 (POST4, +59% ± 40%; POST8, +35% ± 39%; POST12, +18% ± 32%; POST16, -3% ± 24% of PRE M-Carn). From week 12 onward, M-Carn was no longer statistically different from PRE. Both linear and exponential models displayed very similar fit and could be used to describe carnosine washout, although the linear model presented a slightly better fit. The decay in M-Carn was mirrored by a similar decay in high-intensity exercise tolerance; M-Carn was moderately and significantly correlated with total mechanical work done (r = 0.505; P = 0.032) and time to exhaustion (r = 0.72; P < 0.001)., Conclusions: Carnosine washout takes 12-16 wk to complete, and it can be described either by linear or exponential curves. Changes in M-Carn seem to be mirrored by changes in high-intensity exercise tolerance. This information can be used to optimize β-alanine supplementation strategies., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

There is a need to further understand the impact of the menstrual cycle and phase of combined oral contraceptive (COC) use on the pre-analytical variability of markers of bone metabolism in order to improve standardisation procedures for clinical practice and research. The aim of this study was to assess bone metabolism marker concentrations across the menstrual cycle and phases of COC use. Carboxy-terminal cross-linking telopeptide of type I collagen (β-CTX), procollagen type 1 N propeptide (P1NP) and Bone alkaline phosphatase (Bone ALP) concentrations were assessed in eumenorrheic women (n = 14) during the early follicular, ovulatory and mid-luteal phases of the menstrual cycle and in COC (Microgynon®) (n = 14) users on day 2-3 of pill consumption (PC1), day 15-16 pill consumption (PC2) and day 3-4 of the pill free interval (PFI). β-CTX was significantly (-16%) lower at PC2 compared to PC1 (P = 0.015) in COC users and was not affected by menstrual cycle phase (P > 0.05). P1NP and Bone ALP were not significantly different across either menstrual cycle phase or phase of COC use (all P > 0.05). There was no difference in pooled bone marker concentrations between eumenorrheic women and COC users (P > 0.05). In contrast to some previous studies, this study showed that bone marker concentrations do not significantly fluctuate across the menstrual cycle. Furthermore, bone resorption markers are significantly affected by phase of COC use, although bone formation markers do not significantly vary by COC phase. Therefore, the phase of COC use should be considered in clinical practice and research when assessing markers of bone metabolism as this can impact circulating concentrations of bone metabolic markers yet is not currently considered in existing guidelines for best practice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Endurance athletes expend large amounts of energy in prolonged high-intensity exercise and, due to the weight-sensitive nature of most endurance sports, often practice periods of dietary restriction. The Female Athlete Triad and Relative Energy Deficiency in Sport models consider endurance athletes at high-risk for suffering from low energy availability and associated health complications, including an increased chance of bone stress injury. Several studies have examined the effects of low energy availability on various parameters of bone structure and markers of bone (re)modelling; however, there are differences in findings and research methods and critical summaries are lacking. It is difficult for athletes to reduce energy expenditure or increase energy intake (to restore energy availability) in an environment where performance is a priority. Development of an alternative tool to help protect bone health would be beneficial. High-impact exercise can be highly osteogenic and energy efficient; however, at present, it is rarely utilized to promote bone health in endurance athletes. Therefore, with a view to reducing the prevalence of bone stress injury, the objectives of this review are to evaluate the effects of low energy availability on bone health in endurance athletes and explore whether a high-impact exercise intervention may help to prevent those effects from occurring.

Background: Diabetes is a major public health issue and there is a need to develop low-cost, novel interventions to prevent or reduce disease progression. Growing evidence shows that supplementation with carnosine, or its rate-limiting precursor β-alanine, can ameliorate aspects of the metabolic dysregulation that occurs in diabetes. There is, however, a need to develop a better understanding of the magnitude of effect and the factors associated with positive outcomes. The purpose of this systematic review and meta-analysis is to evaluate the effect of carnosine or β-alanine supplementation on markers of glycaemic control and insulin resistance in humans and animals., Methods: We will perform a systematic search for randomised and non-randomised controlled trials. Studies will be retrieved by searching electronic databases, clinical trial registers, author review, and cross-referencing. Primary outcomes include changes in (i) fasting glucose, (ii) glycated haemoglobin, and (iii) 2-h glucose following a glucose tolerance test. A set of additional outcomes includes other markers of glycaemic control and insulin resistance. Risk of bias (RoB) will be assessed using the Cochrane RoB 2.0 tool (human studies) and the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) RoB tool (animal studies). Confidence in the cumulative evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. All meta-analyses will be conducted within a Bayesian framework, providing a flexible modelling approach to account for uncertainty in model parameters and underlying structures within the data., Discussion: By including all available human and animal data, we will provide the most comprehensive overview on the topic to date. The results will have implications for those working in prediabetes, diabetes, and metabolic health in general and may lead to the development of new treatment approaches., Dissemination: Study results will be presented at a professional conference and published in a peer-reviewed journal., Systematic Review Registration: CRD42020191588.

Purpose: Intermittent energy restriction commonly refers to ad libitum energy intake punctuated with 24 h periods of severe energy restriction. This can improve markers of metabolic health but the effects on bone metabolism are unknown. This study assessed how 24 h severe energy restriction and subsequent refeeding affected markers of bone turnover., Methods: In a randomised order, 16 lean men and women completed 2, 48 h trials over 3 days. On day 1, participants consumed a 24 h diet providing 100% [EB: 9.27 (1.43) MJ] or 25% [ER: 2.33 (0.34) MJ] of estimated energy requirements. On day 2, participants consumed a standardised breakfast (08:00), followed by an ad libitum lunch (12:00) and dinner (19:30). Participants then fasted overnight, returning on day 3. Plasma concentrations of C-terminal telopeptide of type I collagen (CTX), procollagen type 1 N-terminal propeptide (P1NP) and parathyroid hormone (PTH) were assessed as indices of bone metabolism after an overnight fast on days 1-3, and for 4 h after breakfast on day 2., Results: There were no differences between trials in fasting concentrations of CTX, P1NP or PTH on days 1-3 (P > 0.512). During both trials, consuming breakfast reduced CTX between 1 and 4 h (P < 0.001) and PTH between 1 and 2 h (P < 0.05), but did not affect P1NP (P = 0.773) Postprandial responses for CTX (P = 0.157), P1NP (P = 0.148) and PTH (P = 0.575) were not different between trials. Ad libitum energy intake on day 2 was greater on ER [12.62 (2.46) MJ] than EB [11.91 (2.49) MJ]., Conclusions: Twenty-four hour severe energy restriction does not affect markers of bone metabolism.

Competing Interests: Competing interests: BS has previously received financial support from Natural Alternatives International (NAI), a company that produces β-alanine, to undertake a study unrelated to this review. NAI have also provided β-alanine supplements free of charge for further experimental investigations and supported open access page charges for several of the author’s manuscripts. NAI have not had any input (financial, intellectual or otherwise) into this review.

To test whether high circulating insulin concentrations influence the transport of β-alanine into skeletal muscle at either saturating or subsaturating β-alanine concentrations, we conducted two experiments whereby β-alanine and insulin concentrations were controlled. In experiment 1 , 12 men received supraphysiological amounts of β-alanine intravenously (0.11 g·kg -1 ·min -1 for 150 min), with or without insulin infusion. β-Alanine and carnosine were measured in muscle before and 30 min after infusion. Blood samples were taken throughout the infusion protocol for plasma insulin and β-alanine analyses. β-Alanine content in 24-h urine was assessed. In experiment 2 , six men ingested typical doses of β-alanine (10 mg/kg) before insulin infusion or no infusion. β-Alanine was assessed in muscle before and 120 min following ingestion. In experiment 1 , no differences between conditions were shown for plasma β-alanine, muscle β-alanine, muscle carnosine and urinary β-alanine concentrations (all P > 0.05). In experiment 2 , no differences between conditions were shown for plasma β-alanine or muscle β-alanine concentrations (all P > 0.05). Hyperinsulinemia did not increase β-alanine uptake by skeletal muscle cells, neither when substrate concentrations exceed the V max of β-alanine transporter TauT nor when it was below saturation. These results suggest that increasing insulin concentration is not necessary to maximize β-alanine transport into muscle following β-alanine intake.

Bone (re)modeling markers can help determine how the bone responds to different types, intensities, and durations of exercise. They also might help predict those at risk of bone injury. We synthesized evidence on the acute and chronic bone metabolic responses to exercise, along with how nutritional factors can moderate this response. Recommendations to optimize future research efforts are made.

Carnosine is a dipeptide abundantly found in human skeletal muscle, cardiac muscle and neuronal cells having numerous properties that confers performance enhancing effects, as well as a wide-range of potential therapeutic applications. A reliable and valid method for tissue carnosine quantification is crucial for advancing the knowledge on biological processes involved with carnosine metabolism. In this regard, proton magnetic resonance spectroscopy (1H-MRS) has been used as a non-invasive alternative to quantify carnosine in human skeletal muscle. However, carnosine quantification by 1H-MRS has some potential limitations that warrant a thorough experimental examination of its validity. The present investigation examined the reliability, accuracy and sensitivity for the determination of muscle carnosine in humans using in vitro and in vivo experiments and comparing it to reference method for carnosine quantification (high-performance liquid chromatography - HPLC). We used in vitro 1H-MRS to verify signal linearity and possible noise sources. Carnosine was determined in the m. gastrocnemius by 1H-MRS and HPLC to compare signal quality and convergent validity. 1H-MRS showed adequate discriminant validity, but limited reliability and poor agreement with a reference method. Low signal amplitude, low signal-to-noise ratio, and voxel repositioning are major sources of error.

Purpose: To investigate the effects of chronic beta-alanine (BA) supplementation on muscle taurine content, blood clinical markers and sensory side-effects., Methods: Twenty-five healthy male participants (age 27 ± 4 years, height 1.75 ± 0.09 m, body mass 78.9 ± 11.7 kg) were supplemented with 6.4 g day -1 of sustained-release BA (N = 16; CarnoSyn™, NAI, USA) or placebo (PL; N = 9; maltodextrin) for 24 weeks. Resting muscle biopsies of the m. vastus lateralis were taken at 0, 12 and 24 weeks and analysed for taurine content (BA, N = 12; PL, N = 6) using high-performance liquid chromatography. Resting venous blood samples were taken every 4 weeks and analysed for markers of renal, hepatic and muscle function (BA, N = 15; PL, N = 8; aspartate transaminase; alanine aminotransferase; alkaline phosphatase; lactate dehydrogenase; albumin; globulin; creatinine; estimated glomerular filtration rate and creatine kinase)., Results: There was a significant main effect of group (p = 0.04) on muscle taurine, with overall lower values in PL, although there was no main effect of time or interaction effect (both p > 0.05) and no differences between specific timepoints (week 0, BA: 33.67 ± 8.18 mmol kg -1  dm, PL: 27.75 ± 4.86 mmol kg -1  dm; week 12, BA: 35.93 ± 8.79 mmol kg -1  dm, PL: 27.67 ± 4.75 mmol kg -1  dm; week 24, BA: 35.42 ± 6.16 mmol kg -1  dm, PL: 31.99 ± 5.60 mmol kg -1  dm). There was no effect of treatment, time or any interaction effects on any blood marker (all p > 0.05) and no self-reported side-effects in these participants throughout the study., Conclusions: The current study showed that 24 weeks of BA supplementation at 6.4 g day -1 did not significantly affect muscle taurine content, clinical markers of renal, hepatic and muscle function, nor did it result in chronic sensory side-effects, in healthy individuals. Since athletes are likely to engage in chronic supplementation, these data provide important evidence to suggest that supplementation with BA at these doses for up to 24 weeks is safe for healthy individuals.

Carnosine (β-alanyl-L-histidine) plays an important role in exercise performance and skeletal muscle homeostasis. Dietary supplementation with the rate-limiting precursor β-alanine leads to an increase in skeletal muscle carnosine content, which further potentiates its effects. There is significant interest in carnosine and β-alanine across athletic and clinical populations. Traditionally, attention has been given to performance outcomes with less focus on the underlying mechanism(s). Putative physiological roles in human skeletal muscle include acting as an intracellular pH buffer, modulating energy metabolism, regulating Ca handling and myofilament sensitivity, and scavenging of reactive species. Emerging evidence shows that carnosine could also act as a cytoplasmic Ca-H exchanger and form stable conjugates with exercise-induced reactive aldehydes. The enigmatic nature of carnosine means there is still much to learn regarding its actions and applications in exercise, health, and disease. In this review, we examine the research relating to each physiological role attributed to carnosine, and its precursor β-alanine, in exercising human skeletal muscle.