Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment.

Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding proteins known to interact with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Loci in/near discs large homolog 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P < 5 × 10-8) for BF% and/or BMI. To further evaluate the functional role of postsynaptic density protein-95 (PSD-95; gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PSD-95/disc large/ZO-1 (PDZ) domain-targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising therapeutic avenue for sustained weight loss.

Harnessing the power of proteomics in precision diabetes medicine.

Precision diabetes medicine (PDM) aims to reduce errors in prevention programmes, diagnosis thresholds, prognosis prediction and treatment strategies. However, its advancement and implementation are difficult due to the heterogeneity of complex molecular processes and environmental exposures that influence an individual's disease trajectory. To address this challenge, it is imperative to develop robust screening methods for all areas of PDM. Innovative proteomic technologies, alongside genomics, have proven effective in precision cancer medicine and are showing promise in diabetes research for potential translation. This narrative review highlights how proteomics is well-positioned to help improve PDM. Specifically, a critical assessment of widely adopted affinity-based proteomic technologies in large-scale clinical studies and evidence of the benefits and feasibility of using MS-based plasma proteomics is presented. We also present a case for the use of proteomics to identify predictive protein panels for type 2 diabetes subtyping and the development of clinical prediction models for prevention, diagnosis, prognosis and treatment strategies. Lastly, we discuss the importance of plasma and tissue proteomics and its integration with genomics (proteogenomics) for identifying unique type 2 diabetes intra- and inter-subtype aetiology. We conclude with a call for action formed on advancing proteomics technologies, benchmarking their performance and standardisation across sites, with an emphasis on data sharing and the inclusion of diverse ancestries in large cohort studies. These efforts should foster collaboration with key stakeholders and align with ongoing academic programmes such as the Precision Medicine in Diabetes Initiative consortium.

Effects of sclerostin injection on soleus and extensor digitorum longus muscle tissue in male mice.

Sclerostin, a potent inhibitor of the Wnt signaling pathway, plays a critical role in bone homeostasis. Evidence suggests that sclerostin may also be involved in crosstalk between other tissues, including muscle. This pilot study attempted to examine the effects of sclerostin on soleus and extensor digitorum longus (EDL) muscle tissue from male mice that were given continuous recombinant sclerostin injections for 4 weeks. A total of 48 10-week-old male C57BL/6J mice were assigned to be sedentary or perform 1 h treadmill running per day for 4 weeks and administered subcutaneous injections of either saline or recombinant sclerostin 5 days/week. Sclerostin injection led to a reduction in the soleus myosin heavy chain (MHC) I, MHC I/IIA, MHC IIA/X, and MHC IIB cross-sectional area (p < 0.05) with no exercise effects on these reductions. In contrast, there were no effects of sclerostin injections or exercise on the fast-twitch EDL muscle in terms of size, MHC protein, or markers of Wnt signaling. These findings provide preliminary evidence of sclerostin's endocrine role in muscle via decreases in myofiber cross-sectional area, which seems to be independent of fiber type but muscle type-specific. More studies, however, are needed to confirm these preliminary results.

Toward countering muscle and bone loss with spaceflight: GSK3 as a potential target.

We examined the effects of ∼30 days of spaceflight on glycogen synthase kinase 3 (GSK3) content and inhibitory serine phosphorylation in murine muscle and bone samples from four separate missions (BION-M1, rodent research [RR]1, RR9, and RR18). Spaceflight reduced GSK3ß content across all missions, whereas its serine phosphorylation was elevated with RR18 and BION-M1. The reduction in GSK3ß was linked to the reduction in type IIA fibers commonly observed with spaceflight as these fibers are particularly enriched with GSK3. We then tested the effects of inhibiting GSK3 before this fiber type shift, and we demonstrate that muscle-specific Gsk3 knockdown increased muscle mass, preserved muscle strength, and promoted the oxidative fiber type with Earth-based hindlimb unloading. In bone, GSK3 activation was enhanced after spaceflight; and strikingly, muscle-specific Gsk3 deletion increased bone mineral density in response to hindlimb unloading. Thus, future studies should test the effects of GSK3 inhibition during spaceflight.

Correction: Klentrou et al. Circulating Levels of Bone Markers after Short-Term Intense Training with Increased Dairy Consumption in Adolescent Female Athletes. Children 2021, 8, 961.

There was an error in the original publication [...].

Sclerostin Influences Exercise-Induced Adaptations in Body Composition and White Adipose Tissue Morphology in Male Mice.

Sclerostin is an inhibitor of the osteogenic Wnt/ß-catenin signaling pathway that also has an endocrine role in regulating adipocyte differentiation and metabolism. Additionally, subcutaneous white adipose tissue (scWAT) sclerostin content decreases following exercise training (EXT). Therefore, we hypothesized that EXT-induced reductions in adipose tissue sclerostin may play a role in regulating adaptations in body composition and whole-body metabolism. To test this hypothesis, 10-week-old male C57BL/6J mice were either sedentary (SED) or performing 1 hour of treadmill running at ~65% to 70% maximum oxygen consumption (VO2max ) 5 day/week (EXT) for 4 weeks and had subcutaneous injections of either saline (C) or recombinant sclerostin (S) (0.1 mg/kg body mass) 5 day/week; thus, making four groups (SED-C, EXT-C, SED-S, and EXT-S; n = 12/group). No differences in body mass were observed between experimental groups, whereas food intake was higher in EXT (p = 0.03) and S (p = 0.08) groups. There was a higher resting energy expenditure in all groups compared to SED-C. EXT-C had increased lean mass and decreased fat mass percentage compared to SED-C and SED-S. No differences in body composition were observed in either the SED-S or EXT-S groups. Lower scWAT (inguinal), epididymal white adipose tissue (eWAT) (visceral epididymal) mass, and scWAT adipocyte cell size and increased percentage of multilocular cells in scWAT were observed in the EXT-C group compared to SED-C, whereas lower eWAT was only observed in the EXT-S group. EXT mice had increased scWAT low-density lipoprotein receptor-related protein 4 (Lrp4) and mitochondrial content and sclerostin treatment only inhibited increased Lrp4 content with EXT. Together, these results provide evidence that reductions in resting sclerostin with exercise training may influence associated alterations in energy metabolism and body composition, particularly in scWAT. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Correction: McKinlay et al. Effects of Post-Exercise Whey Protein Consumption on Recovery Indices in Adolescent Swimmers. Int. J. Environ. Res. Public Health 2020, 17, 7761.

The authors of "Effects of Post-Exercise Whey Protein Consumption on Recovery Indices in Adolescent Swimmers" report an error in Table 1 of their article [...].

Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection.

NEW FINDINGS: What is the central question in this study? Promoting muscle health with regular aerobic exercise can improve mental health through a kynurenine metabolic pathway: do conditions of muscle disease such as muscular dystrophy negatively influence this pathway? What is the main finding and its importance? The DBA/2J mdx model of Duchenne muscular dystrophy exhibits altered kynurenine metabolism with less kynurenic acid and peroxisome proliferator-activated receptor-γ coactivator 1-α and higher levels of tumour necrosis factor α mRNA - results associated with anxiety-like behaviour. ABSTRACT: Regular exercise can direct muscle kynurenine (KYN) metabolism toward the neuroprotective branch of the kynurenine pathway thereby limiting the accumulation of neurotoxic metabolites in the brain and contributing to mental resilience. However, the effect of muscle disease on KYN metabolism has not yet been investigated. Previous work has highlighted anxiety-like behaviours in approximately 25% of patients with Duchenne muscular dystrophy (DMD), possibly due to altered KYN metabolism. Here, we characterized KYN metabolism in mdx mouse models of DMD. Young (8-10 week old) DBA/2J (D2) mdx mice, but not age-matched C57BL/10 (C57) mdx mice, had lower levels of circulating kynurenic acid (KYNA) and lower KYNA:KYN ratio compared with their respective wild-type (WT) controls. While both C57 and D2 mdx mice displayed signs of anxiety-like behaviour, spending more time in the corners of the arena during a novel object recognition test, this effect was more prominent in D2 mdx mice. Correlational analysis detected a significant negative association between KYNA:KYN levels and time spent in corners in D2 mice, but not C57 mice. In extensor digitorum longus muscles from D2 mdx mice, but not C57 mdx mice, we found lowered protein levels of peroxisome proliferator-activated receptor-γ coactivator 1-α and kynurenine amino transferase-1 enzyme when compared with WT. Furthermore, D2 mdx quadriceps muscles had the highest level of tumour necrosis factor α expression, which is suggestive of enhanced inflammation. Thus, our pilot work shows that KYN metabolism is altered in D2 mdx mice, with a potential contribution from altered muscle health.

Intensified training in adolescent female athletes: a crossover study of Greek yogurt effects on indices of recovery.

Background: During a period of intensified exercise (e.g. training/identification camps), often undertaken by competitive youth athletes, the maintenance of muscle function and peak performance can become challenging due to an accumulation of fatigue. The provision of post-exercise dairy protein in adults has been previously shown to accelerate recovery; however, its efficacy in youth athletes is currently unknown. Therefore, the purpose of this study was to examine the effects of increased dairy protein consumption with plain Greek yogurt (GY) on performance and recovery indices during an intensified soccer training camp in adolescent female soccer players. Methods: Thirteen players (14.3 ± 1.3 years) participated in a randomized, double blinded, crossover design study where they received 3 servings/day of either GY (~115 kcal, 17 g protein, ~11.5 g carbohydrates) or an isoenergetic carbohydrate control (CHO, ~115 kcal, 0.04 g protein, ~28.6 g carbohydrates) during two 5-day soccer-specific training camps. Performance was assessed before and after each training camp. Fasted, morning, creatine kinase (CK), insulin-like growth factor-1 (IGF-1), C-reactive protein (CRP), interleukin 6 (IL6), interleukin 10 (IL10) and tumor necrosis factor-α (TNFα) were measured in plasma pre- and post-training. Results: Training led to decrements in counter-movement jump (p = 0.01), broad jump (p = 0.04) and aerobic capacity (p = 0.006), with no effect of GY. A significant increase in anti-inflammatory cytokine IL10 was observed from pre- to post-training in GY (+26% [p = 0.008]) but not in CHO (p = 0.89). CRP and CK increased (+65% [p = 0.005] and +119% [p ≤ 0.001], respectively), while IGF-1 decreased (-34% [p ≤ 0.001]) from pre- to post-training with no difference between conditions. Conclusions: These results demonstrate that consumption of GY did not offer any added recovery benefit with respect to measures of performance and in the attenuation of exercise-induced muscle damage above that achieved with energy-matched carbohydrate in this group of young female soccer players. However, regular consumption of GY may assist with the acute anti-inflammatory response during periods of intensified training in adolescent athletes.

Acute Effects of Milk vs. Carbohydrate on Bone Turnover Biomarkers Following Loading Exercise in Young Adult Females.

Dairy products and impact exercise have previously been identified to be independently beneficial for bone mineral properties, however, it is unknown how the combination of these two osteogenic interventions may alter acute bone turnover. Using a randomized crossover design, we compared the acute effects of consuming milk vs. an isoenergetic carbohydrate control beverage on bone biomarkers following loading exercise. Thirteen healthy female participants (Age = 20.3 ± 2.3y; BMI = 21.0 ± 1.1 kg/m2) consumed either 550 mL of 0% skim white milk (MILK) or 52.7 g of maltodextrin in 550 mL of water (CHO), both 5 min and 1 h following completion of a combined plyometric (198 impacts) and resistance exercise (3-4 sets/exercise, 8-12 reps/set, ∼75% 1-RM) bout. Venous blood samples were obtained pre-exercise, and 15 min, 75 min, 24 h and 48 h post-exercise to assess serum concentrations of bone resorption biomarkers, specifically carboxyl-terminal crosslinking telopeptide of type I collagen (CTX), receptor activator nuclear factor kappa-ß ligand (RANKL), and sclerostin (SOST), as well as bone formation biomarkers, specifically osteoprotegerin (OPG) and osteocalcin (OC). When absolute biomarker concentrations were examined, there were no interaction or group effects for any biomarker, however, there were main time effects (p < 0.05) for RANKL, SOST, and OC, which were lower, and the OPG: OPG/RANKL ratio, which was higher at 75 min post-exercise compared with baseline in both conditions. In addition to assessing absolute biomarker concentrations at specific timepoints, we also evaluated the relative (% change) cumulative post-exercise response (75 min to 48 h) using an area under the curve (AUC) analysis. This analysis showed that the relative post-exercise CTX response was significantly lower in the MILK compared to the CHO condition (p = 0.03), with no differences observed in the other biomarkers. These results show that while milk does not appear to alter absolute concentrations of bone biomarkers compared to CHO, it may attenuate relative post-exercise bone resorption (i.e., blunt the usual catabolic response to exercise).

Menstrual Cycle Related Fluctuations in Circulating Markers of Bone Metabolism at Rest and in Response to Running in Eumenorrheic Females.

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 V̇O2max. Resting and post-exercise (0, 30, 90 min) sclerostin, parathyroid hormone (PTH), carboxy-terminal cross-linking telopeptide of type I collagen (ß-CTXI), and procollagen type 1 N propeptide (PINP) were assessed in 10 eumenorrheic women (age: 21 ± 3 y, BMI: 23.2 ± 3.0 kg.m2) 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), ß-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, ß-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. ß-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.

Subcutaneous adipose tissue sclerostin is reduced and Wnt signaling is enhanced following 4-weeks of sprint interval training in young men with obesity.

Sclerostin is a Wnt/ß-catenin antagonist, mainly secreted by osteocytes, and most known for its role in reducing bone formation. Studies in rodents suggest sclerostin can also regulate adipose tissue mass and metabolism, representing bone-adipose tissue crosstalk. Exercise training has been shown to reduce plasma sclerostin levels; but the effects of exercise on sclerostin and Wnt/ß-catenin signaling specifically within adipose tissue has yet to be examined. The purpose of this study was to examine subcutaneous WAT (scWAT) sclerostin content and Wnt signaling in response to exercise training in young men with obesity. To this end, 7 male participants (BMI = 35 ± 4; 25 ± 4 years) underwent 4 weeks of sprint interval training (SIT) involving 4 weekly sessions consisting of a 5-min warmup, followed by 8 × 20 s intervals at 170% of work rate at VO2peak , separated by 10 s of rest. Serum and scWAT were sampled at rest both pre- and post-SIT. Despite no changes in serum sclerostin levels, we found a significant decrease in adipose sclerostin content (-37%, p = 0.04), an increase in total ß-catenin (+52%, p = 0.03), and no changes in GSK3ß serine 9 phosphorylation. There were also concomitant reductions in serum TNF-α (-0.36 pg/ml, p = 0.03) and IL-6 (-1.44 pg/ml, p = 0.05) as well as an increase in VO2peak (+5%, p = 0.03) and scWAT COXIV protein content (+95%, p = 0.04). In conclusion, scWAT sclerostin content was reduced and ß-catenin content was increased following SIT in young men with excess adiposity, suggesting a role of sclerostin in regulating human adipose tissue in response to exercise training.

Characterization of sclerostin's response within white adipose tissue to an obesogenic diet at rest and in response to acute exercise in male mice.

Introduction: It is well established that sclerostin antagonizes the anabolic Wnt signalling pathway in bone, however, its physiological role in other tissues remains less clear. This study examined the effect of a high-fat diet (HFD) on sclerostin content and downstream markers of the Wnt signaling pathway (GSK3ß and ß-catenin) within subcutaneous inguinal white adipose tissue (iWAT), and visceral epididymal WAT (eWAT) depots at rest and in response to acute aerobic exercise. Methods: Male C57BL/6 mice (n = 40, 18 weeks of age) underwent 10 weeks of either a low-fat diet (LFD) or HFD. Within each diet group, mice were assigned to either remain sedentary (SED) or perform 2 h of endurance treadmill exercise at 15 m min-1 with 5° incline (EX), creating four groups: LFD + SED (N = 10), LFD + EX (N = 10), HFD + SED (N = 10), and HFD + EX (N = 10). Serum and WAT depots were collected 2 h post-exercise. Results: Serum sclerostin showed a diet-by-exercise interaction, reflecting HFD + EX mice having higher concentration than HFD + SED (+31%, p = 0.03), and LFD mice being unresponsive to exercise. iWAT sclerostin content decreased post-exercise in both 28 kDa (-31%, p = 0.04) and 30 kDa bands (-36%, main effect for exercise, p = 0.02). iWAT ß-catenin (+44%, p = 0.03) and GSK3ß content were higher in HFD mice compared to LFD (+128%, main effect for diet, p = 0.005). Monomeric sclerostin content was abolished in eWAT of HFD mice (-96%, main effect for diet, p < 0.0001), was only detectable as a 30 kDa band in LFD mice and was unresponsive to exercise. ß-catenin and GSK3ß were both unresponsive to diet and exercise within eWAT. Conclusion: These results characterized sclerostin's content to WAT depots in response to acute exercise, which appears to be specific to a reduction in iWAT and identified a differential regulation of sclerostin's form/post-translational modifications depending on diet and WAT depot.

Twelve weeks of a diet and exercise intervention alters the acute bone response to exercise in adolescent females with overweight/obesity.

Introduction: Exercise and consumption of dairy foods have been shown to improve bone mineralization. However, little is known about the magnitude and timing of their synergistic effects on markers and regulators of bone metabolism in response to acute exercise in adolescent females with obesity, a population susceptible to altered bone metabolism and mineral properties. This study examined the influence of twelve weeks of exercise training and nutritional counselling on the bone biochemical marker response to acute exercise and whether higher dairy consumption could further influence the response. Methods: Thirty adolescent females (14.3 ± 2.0 years) with overweight/obesity (OW/OB) completed a 12-week lifestyle modification intervention involving exercise training and nutritional counselling. Participants were randomized into two groups: higher dairy intake (RDa; 4 servings/day; n = 14) or low dairy intake (LDa; 0-2 servings/d; n = 16). Participants performed one bout of plyometric exercise (5 circuits; 120 jumps) both pre- and post-intervention. Blood samples were taken at rest, 5 min and 1 h post-exercise. Serum sclerostin, osteocalcin (OC), osteoprotegerin (OPG), receptor activator nuclear factor kappa B ligand (RANKL), and C-terminal telopeptide of type 1 collagen (ßCTX) concentrations were measured. Results: While there was an overall increase in sclerostin pre-intervention from pre to 5 min post-exercise (+11% p = 0.04), this response was significantly decreased post-intervention (-25%, p = 0.03) independent of dairy intake. The OPG:RANKL ratio was unresponsive to acute exercise pre-intervention but increased 1 h post-exercise (+2.6 AU; p < 0.001) post-intervention. Dairy intake did not further influence these absolute responses. However, after the 12-week intervention, the RDa group showed a decrease in the relative RANKL post-exercise response (-21.9%; p < 0.01), leading to a consistent increase in the relative OPG:RANKL ratio response, which was not the case in the LDa group. There was no influence of the intervention or dairy product intake on OC, OPG, or ßCTX responses to acute exercise (p > 0.05). Conclusion: A lifestyle modification intervention involving exercise training blunts the increase in sclerostin and can augment the increase in OPG:RANKL ratio to acute exercise in adolescent females with OW/OB, while dairy product consumption did not further influence these responses.

Circulating Levels of Bone Markers after Short-Term Intense Training with Increased Dairy Consumption in Adolescent Female Athletes.

Thirteen female adolescent soccer players (14.3 ± 1.3 years) participated in a cross-over, double-blind trial examining the effects of Greek yogurt (GY) consumption on bone biomarkers during 5 days of intense soccer training. The study took place over two intervention weeks, which consisted of a pre-training assessment day, 5 training days, and a post-training assessment day. Participants completed the GY condition and a carbohydrate isocaloric placebo control pudding condition (CHO) in random order, 4 weeks apart. Morning, fasted, resting blood samples were collected pre- and post-training in each condition. Total osteocalcin (tOC), undercarboxylated osteocalcin (unOC), C-terminal telopeptide of type 1 collagen (CTX), osteoprotegerin (OPG), and receptor activator nuclear factor kappa-ß ligand (RANKL) were measured in serum. The results showed no effects for time (pre- to post-training) or condition, and no interaction for tOC, CTX, OPG, RANKL, and the OPG/RANKL ratio. A time-by-condition interaction (p = 0.011) was observed in unOC, reflecting a post-training decrease in the GY, but not the CHO condition (-26% vs. -3%, respectively). However, relative unOC (% of tOC) decreased post-training (-16%), with no differences between conditions. These findings suggest that short-term high-impact intense training had no direct catabolic impact on bone metabolism, with GY adding no benefit beyond that of the isocaloric CHO control pudding.

Cytokine concentrations in saliva vs. plasma at rest and in response to intense exercise in adolescent athletes.

BACKGROUND: Salivary measures are advantageous in conducting large paediatric studies involving repeated measures. However, research measuring salivary cytokines in youth is limited. AIM: Compare salivary with plasma concentrations of inflammatory cytokines at rest and following exercise in adolescent swimmers (21 male, 22 female). METHODS: Following collection of resting saliva and blood samples, participants performed a bout of high-intensity interval swimming, with samples taken again ∼15 min post-swimming and analysed for interleukin-6 (IL-6), interleukin 10 (IL-10), and tumour necrosis factor-alpha (TNF-α). RESULTS: Resting IL-10 was significantly lower, while IL-6 and TNF-α were significantly higher in saliva compared with plasma. IL-10 increased from pre- to post-swimming in plasma, but less so in saliva (51% vs. 29%; p = 0.02). TNF-α decreased post-swimming in saliva, but not in plasma (-27% vs -1%; p = 0.01). IL-6 decreased post-swimming in saliva compared with plasma (-21% vs. -3%; p = 0.06). Intraclass correlation coefficients (ICC) revealed no association between salivary and plasma IL-6 and TNF-α, while IL-10 showed a weak correlation only at rest (ICC = 0.39; p = 0.05). CONCLUSIONS: Differences in concentrations and exercise responses, along with weak correlations, suggest that salivary cytokine levels are not an accurate representation of blood cytokine levels, and should not be used as a surrogate measure in paediatric studies.

High-intensity interval training or resistance training versus usual care in men with prostate cancer on active surveillance: a 3-arm feasibility randomized controlled trial.

This study assessed the feasibility of a phase II randomized controlled trial of high-intensity interval training (HIIT), resistance training (RT), and usual care (UC) in men with prostate cancer (PCa) on active surveillance and evaluated changes in clinically relevant outcomes. Eighteen men undergoing active surveillance for PCa were randomized to HIIT (n = 5), RT (n = 7), or UC (n = 6). Exercise participants attended 2 supervised sessions weekly and were instructed to complete 1 home-based session weekly for 8 weeks. UC participants were provided with physical activity guidelines. Feasibility was met for attendance, compliance, and retention, but not recruitment. HIIT increased leg press (mean: +8.2 kg, 95% CI 1.1 to 15.3) from baseline to 8 weeks. RT increased seated row (mean: +11.7 kg, 95% CI 6.1 to 17.3), chest press (mean: +10.4 kg, 95% CI 5.3 to 15.5), leg press (mean: +13.1 kg, 95% CI 5.9 to 20.3), serum insulin-like binding protein-3 (IGFBP-3) (mean: +400.0 ng/mL, 95% CI 94.5 to 705.5), and decreased interferon-γ (mean: -3.1 pg/mL, 95% CI -5.7 to -0.4). No changes were observed in the UC group. HIIT and RT may be effective strategies for improving muscle strength; however, only RT may increase serum IGFBP-3. Strategies that can enhance recruitment in men on active surveillance are important prior to conducting a phase II trial. Trial registration number: ClinicalTrials.gov number NCT04266262. Novelty: High-intensity interval training or resistance training are feasible during active surveillance for prostate cancer. Resistance training may suppress the tumour-promoting effects of insulin-like growth factor-I (IGF-I) via increased expression of IGFBP-3.

Neutral Effect of Increased Dairy Product Intake, as Part of a Lifestyle Modification Program, on Cardiometabolic Health in Adolescent Girls With Overweight/Obesity: A Secondary Analysis From a Randomized Controlled Trial.

Background: The presence of obesity and some cardiometabolic disease risk factors in childhood and adolescence track into adulthood. Intake of dairy products has been shown to be inversely related to adiposity and cardiometabolic variables in youth. However, limited research has examined cardiometabolic disease risk factors following increased dairy product consumption as part of a lifestyle modification intervention in youth with overweight/obesity. This secondary analysis aimed to determine whether 12 weeks of increased dairy consumption, as part of a lifestyle modification program, affects cardiometabolic variables in adolescent females (range: 10-18 years) with overweight/obesity (BMI > 85th centile). Methods: Participants were randomized into two groups: higher dairy intake (RDa; four servings/day [to reflect previous Canada's Food Guide recommendations]; n = 23) or low dairy intake (LDa; 0-2 servings/day; n = 23). Both RDa and LDa participated in a 12-week, eucaloric, lifestyle modification intervention consisting of exercise training, and nutritional counseling. Adiposity (percent body fat [%BF]), dietary intake, and measures of cardiometabolic health were measured pre- and post-intervention. Results: There were no significant changes over time within groups or differences over time between groups for triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), TC/HDL ratio, low-density lipoprotein cholesterol (LDL), glucose, insulin, homeostatic model assessment of insulin resistance, adiponectin, and tumor necrosis factor alpha (TNF-α) (main effects of time and interactions, p > 0.05). Leptin decreased over the 12-week lifestyle intervention in both groups (main effect of time, p = 0.02). After combining the groups (n = 46), significant correlations were found between change in %BF and change in some cardiometabolic variables (HDL [r = -0.40], TC/HDL ratio [r = 0.42], LDL [r = 0.36], and TNF-α [r = 0.35], p < 0.05). After controlling for change in dairy product intake, the correlations were unchanged. Conclusion: Our findings demonstrate that increased dairy product consumption, as part of a lifestyle modification, weight management intervention, had a neutral effect on cardiometabolic disease risk factors in adolescent females with overweight/obesity. Change in dairy product intake did not influence the relationships between change in adiposity and change in cardiometabolic variables. Future research designed to primarily assess the effect of increased dairy product consumption on cardiometabolic disease risk factors in this population is warranted. Clinical Trial Registration: Clinicaltrials.gov; NCT#02581813.

Cytokines, Adipokines, and Bone Markers at Rest and in Response to Plyometric Exercise in Obese vs Normal Weight Adolescent Females.

Background: In adults, excess adiposity has been associated with low-grade, chronic inflammation and compromised bone health, but less is known about these linkages in children. The purpose of this study was to compare the circulating levels of inflammatory cytokines, adipokines, osteokines, and bone markers at rest and in response to plyometric exercise between obese and normal weight adolescent females. Methods: Ten normal weight (BMI = 21.3 ± 2) and 10 obese (BMI = 32.9 ± 4), postmenarcheal females, aged 13-17 years, performed one bout of plyometric exercise (5 circuits; 120 jumps). Blood samples were taken at rest, 5 min, 1 h, and 24 h post-exercise. Tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), insulin, leptin, osteocalcin, carboxy-terminal telopeptide (CTX), sclerostin, and parathyroid hormone (PTH) were measured in serum. Results: Cytokines were not different between groups at rest or over time with IL-6 increasing (+31%; p = 0.04) 5 min post-exercise and TNF-α decreasing (-9%; p = 0.001) 1 h post-exercise. Insulin and leptin were higher in the obese compared to the normal weight females. In both groups, insulin significantly increased 5 min post-exercise but remained elevated 1 h post-exercise only in the obese group. Leptin did not change in response to exercise. Osteocalcin was lower in the obese group across time and increased (+12%; p = 0.02) 24 h post-exercise in both groups. CTX was similar between groups at rest and decreased (-24%; p < 0.001) 1 h post-exercise. Sclerostin was similar between groups at rest, but there was a significant interaction reflecting a significant increase (+29%; p = 0.04) 5 min post-exercise in the obese group and a non-significant decrease (-13%; p = 0.08) in normal weight controls. PTH increased 5 min post-exercise, dropped 1 h post-exercise to lower than pre-exercise, and returned to baseline 24 h post-exercise in both groups. Conclusion: Obese adolescent females from our study had no evidence of resting inflammation or differences in bone resorption but show blunted bone formation when compared to normal weight controls. The direction and temporal changes in inflammatory cytokines, adipokines, and bone turnover markers to exercise were similar in both groups, reflecting an overall bone anabolic response for most biomarkers, except sclerostin, which increased only in the obese females immediately post-exercise, suggesting a different systemic regulation of sclerostin depending on adiposity.

Effects of Post-Exercise Whey Protein Consumption on Recovery Indices in Adolescent Swimmers.

Purpose: This study examined the effect of whey protein consumption following high-intensity interval swimming (HIIS) on muscle damage, inflammatory cytokines and performance in adolescent swimmers. Methods: Fifty-four swimmers (11-17 years-old) were stratified by age, sex and body mass to a whey protein (PRO), isoenergetic carbohydrate (CHO) or a water/placebo (H2O) group. Following baseline blood samples (06:00 h) and a standardised breakfast, participants performed a maximal 200 m swim, followed by HIIS. A total of two post-exercise boluses were consumed following HIIS and ~5 h post-baseline. Blood and 200 m performance measurements were repeated at 5 h, 8 h and 24 h from baseline. Muscle soreness was assessed at 24 h. Creatine kinase (CK), interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-α) were measured in plasma. Results: No difference in 200 m swim performance was observed between groups. CK activity was elevated at 5 h compared to baseline and 24 h and at 8 h compared to all other timepoints, with no differences between groups. Muscle soreness was lower in PRO compared to H2O (p = 0.04). Anti-inflammatory IL-10 increased at 8 h in PRO, while it decreased in CHO and H2O. Conclusions: Post-exercise consumption of whey protein appears to have no additional benefit on recovery indices following HIIS compared to isoenergetic amounts of carbohydrate in adolescent swimmers. However, it may assist with the acute-inflammatory response.