Changes in the medial prefrontal cortex metabolites after 6 months of medication therapy for patients with bipolar disorder: A 1H-MRS study.

AIMS: The study aimed to assess brain metabolite differences in the medial prefrontal cortex (mPFC) between acute and euthymic episodes of bipolar disorder (BD) with both mania and depression over a 6-month medication treatment period. METHODS: We utilized 1H-MRS technology to assess the metabolite levels in 53 individuals with BD (32 in depressive phase, 21 in manic phase) and 34 healthy controls (HCs) at baseline. After 6 months of medication treatment, 40 subjects underwent a follow-up scan in euthymic state. Metabolite levels, including N-acetyl aspartate (NAA), glutamate (Glu), and Glutamine (Gln), were measured in the mPFC. RESULTS: Patients experiencing depressive and manic episodes exhibited a notable reduction in NAA/Cr + PCr ratios at baseline compared to healthy controls (p = 0.004; p = 0.006) in baseline, compared with HCs. Over the 6-month follow-up period, the manic group displayed a significant decrease in Gln/Cr + PCr compared to the initial acute phase (p = 0.03). No significant alterations were found in depressed group between baseline and follow-up. CONCLUSION: This study suggests that NAA/Cr + PCr ratios and Gln/Cr + PCr ratios in the mPFC may be associated with manic and depressive episodes, implicating that Gln and NAA might be useful biomarkers for distinguishing mood phases in BD and elucidating its mechanisms.

Pro-atherogenic medical conditions are associated with widespread regional brain metabolite abnormalities in those with alcohol use disorder.

AIMS: Widespread brain metabolite abnormalities in those with alcohol use disorder (AUD) were reported in numerous studies, but the effects of the pro-atherogenic conditions of hypertension, type 2 diabetes mellitus, hepatitis C seropositivity, and hyperlipidemia on metabolite levels were not considered. These conditions were associated with brain metabolite abnormalities in those without AUD. We predicted treatment-seeking individuals with AUD and pro-atherogenic conditions (Atherogenic+) demonstrate lower regional metabolite markers of neuronal viability [N-acetylaspartate (NAA)] and cell membrane turnover/synthesis [choline-containing compounds (Cho)], compared with those with AUD without pro-atherogenic conditions (Atherogenic-) and healthy controls (CON). METHODS: Atherogenic+ (n = 59) and Atherogenic- (n = 51) and CON (n = 49) completed a 1.5 T proton magnetic resonance spectroscopic imaging study. Groups were compared on NAA, Cho, total creatine, and myoinositol in cortical gray matter (GM), white matter (WM), and select subcortical regions. RESULTS: Atherogenic+ had lower frontal GM and temporal WM NAA than CON. Atherogenic+ showed lower parietal GM, frontal, parietal and occipital WM and lenticular nuclei NAA level than Atherogenic- and CON. Atherogenic- showed lower frontal GM and WM NAA than CON. Atherogenic+ had lower Cho level than CON in the frontal GM, parietal WM, and thalamus. Atherogenic+ showed lower frontal WM and cerebellar vermis Cho than Atherogenic- and CON. CONCLUSIONS: Findings suggest proatherogenic conditions in those with AUD were associated with increased compromise of neuronal integrity and cell membrane turnover/synthesis. The greater metabolite abnormalities observed in Atherogenic+ may relate to increased oxidative stress-related compromise of neuronal and glial cell structure and/or impaired arterial vasoreactivity/lumen viability.

Diffusion magnetic resonance spectroscopy captures microglial reactivity related to gut-derived systemic lipopolysaccharide: A preliminary study.

Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.

Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

Few human studies have assessed the association of prenatal maternal immune activation (MIA) with measures of brain development and psychiatric risk in newborn offspring. Our goal was to identify the effects of MIA during the 2nd and 3rd trimesters of pregnancy on newborn measures of brain metabolite concentrations, tissue microstructure, and motor development. This was a prospective longitudinal cohort study conducted with nulliparous pregnant women who were aged 14 to 19 years and recruited in their 2nd trimester, as well as their children who were followed through 14 months of age. MIA was indexed by maternal interleukin-6 (IL-6) and C-reactive protein (CRP) in both trimesters of pregnancy. Primary outcomes included: (1) newborn brain metabolite concentrations as ratios to creatine (N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr) measured using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity, measured using Diffusion Tensor Imaging; and (3) indices of motor development, assessed prenatally and postnatally at ages 4- and 14-months. Maternal IL-6 and CRP levels associated significantly with both metabolites in the putamen, thalamus, insula, and the internal capsule. Maternal IL-6 associated significantly with fractional anisotropy in the putamen, caudate, thalamus, insula, and precuneus, and with mean diffusivity in the inferior parietal and middle temporal gyrus. CRP associated significantly with fractional anisotropy in the thalamus, insula, and putamen. Significant associations were found in common regions across imaging modalities, though the direction of associations differed by immune marker. In addition, both maternal IL-6 and CRP (in both trimesters) prenatally associated significantly with offspring motor development at 4- and 14-months of age. The left thalamus mediated effects of IL-6 on postnatal motor development. These findings demonstrate that levels of MIA in mid- to late pregnancy in a generally healthy sample associate with tissue characteristics in newborn brain regions that primarily support motor integration and coordination, as well as behavioral regulation. Those brain effects may contribute to differences in motor development.

Mitohormesis during advanced stages of Duchenne muscular dystrophy reveals a redox-sensitive creatine pathway that can be enhanced by the mitochondrial-targeting peptide SBT-20.

Mitochondrial creatine kinase (mtCK) regulates the "fast" export of phosphocreatine to support cytoplasmic phosphorylation of ADP to ATP which is more rapid than direct ATP export. Such "creatine-dependent" phosphate shuttling is attenuated in several muscles, including the heart, of the D2.mdx mouse model of Duchenne muscular dystrophy at only 4 weeks of age. However, the degree to which creatine-dependent and -independent systems of phosphate shuttling progressively worsen or potentially adapt in a hormetic manner throughout disease progression remains unknown. Here, we performed a series of proof-of-principle investigations designed to determine how phosphate shuttling pathways worsen or adapt in later disease stages in D2.mdx (12 months of age). We also determined whether changes in creatine-dependent phosphate shuttling are linked to alterations in mtCK thiol redox state. In permeabilized muscle fibres prepared from cardiac left ventricles, we found that 12-month-old male D2.mdx mice have reduced creatine-dependent pyruvate oxidation and elevated complex I-supported H2O2 emission (mH2O2). Surprisingly, creatine-independent ADP-stimulated respiration was increased and mH2O2 was lowered suggesting that impairments in the faster mtCK-mediated phosphocreatine export system resulted in compensation of the alternative slower pathway of ATP export. The apparent impairments in mtCK-dependent bioenergetics occurred independent of mtCK protein content but were related to greater thiol oxidation of mtCK and a more oxidized cellular environment (lower GSH:GSSG). Next, we performed a proof-of-principle study to determine whether creatine-dependent bioenergetics could be enhanced through chronic administration of the mitochondrial-targeting, ROS-lowering tetrapeptide, SBT-20. We found that 12 weeks of daily treatment with SBT-20 (from day 4-∼12 weeks of age) increased respiration and lowered mH2O2 only in the presence of creatine in D2.mdx mice without affecting calcium-induced mitochondrial permeability transition activity. In summary, creatine-dependent mitochondrial bioenergetics are attenuated in older D2.mdx mice in relation to mtCK thiol oxidation that seem to be countered by increased creatine-independent phosphate shuttling as a unique form of mitohormesis. Separate results demonstrate that creatine-dependent bioenergetics can also be enhanced with a ROS-lowering mitochondrial-targeting peptide. These results demonstrate a specific relationship between redox stress and mitochondrial hormetic reprogramming during dystrophin deficiency with proof-of-principle evidence that creatine-dependent bioenergetics could be modified with mitochondrial-targeting small peptide therapeutics.

Mitigating Traumatic Brain Injury: A Narrative Review of Supplementation and Dietary Protocols.

Traumatic brain injuries (TBIs) constitute a significant public health issue and a major source of disability and death in the United States and worldwide. TBIs are strongly associated with high morbidity and mortality rates, resulting in a host of negative health outcomes and long-term complications and placing a heavy financial burden on healthcare systems. One promising avenue for the prevention and treatment of brain injuries is the design of TBI-specific supplementation and dietary protocols centred around nutraceuticals and biochemical compounds whose mechanisms of action have been shown to interfere with, and potentially alleviate, some of the neurophysiological processes triggered by TBI. For example, evidence suggests that creatine monohydrate and omega-3 fatty acids (DHA and EPA) help decrease inflammation, reduce neural damage and maintain adequate energy supply to the brain following injury. Similarly, melatonin supplementation may improve some of the sleep disturbances often experienced post-TBI. The scope of this narrative review is to summarise the available literature on the neuroprotective effects of selected nutrients in the context of TBI-related outcomes and provide an evidence-based overview of supplementation and dietary protocols that may be considered in individuals affected by-or at high risk for-concussion and more severe head traumas. Prophylactic and/or therapeutic compounds under investigation include creatine monohydrate, omega-3 fatty acids, BCAAs, riboflavin, choline, magnesium, berry anthocyanins, Boswellia serrata, enzogenol, N-Acetylcysteine and melatonin. Results from this analysis are also placed in the context of assessing and addressing important health-related and physiological parameters in the peri-impact period such as premorbid nutrient and metabolic health status, blood glucose regulation and thermoregulation following injury, caffeine consumption and sleep behaviours. As clinical evidence in this research field is rapidly emerging, a comprehensive approach including appropriate nutritional interventions has the potential to mitigate some of the physical, neurological, and emotional damage inflicted by TBIs, promote timely and effective recovery, and inform policymakers in the development of prevention strategies.

Combined Impact of Creatine, Caffeine, and Variable Resistance on Repeated Sprint Ability in Young Soccer Players.

There is evidence that both intra-serial variable resistance (I-sVR), as pre-activation within the post-activation performance enhancement cycle (PAPE), and creatine and caffeine supplementation increase athletic performance in isolation. However, the effect of the three conditioning factors on 30 m repeated sprint ability (RSA) performance in young soccer players is unknown. This study determined the summative and isolation effect of ergogenic aids and pre-activation in half-back squats (HBSs) with I-sVR on performance in an RSA test in young soccer players. Twenty-eight young soccer players were randomly assigned to either EG1 (n = 7, creatine + caffeine + I-sVR), EG2 (n = 7, creatine + placebo2 + I-sVR), EG3 (n = 7, placebo1 + caffeine + I-sVR), or EG4 (n = 7, placebo1 + placebo2 + I-sVR), using a factorial, four-group-matched, double-blind, placebo-controlled design. Creatine supplementation included 0.3 g/kg/day for 14 days, caffeine supplementation included 0.3 mg/kg per day, and pre-activation in HBS with I-sVR (1 × 5 at 30% 1RM [1.0-1.1 m/s] + 1 × 4 at 60% 1RM [0.6-0.7 m/s]). The RSA test and HBS outcomes were evaluated. Three-way ANOVA showed non-significant differences for the RSA test and HBS outcomes (p > 0.05). At the end of this study, it was found that the three ergogenic aids, together, do not generate a summative effect on the physical performance of young soccer players. However, it is important to analyze individual responses to these specific protocols.

Association of Genetic Profile with Muscle Mass Gain and Muscle Injury Prevention in Professional Football Players after Creatine Supplementation.

BACKGROUND: In recent years, the study of creatine supplementation in professional athletes has been of great interest. However, the genetics involved in response to supplementation is unknown. The aim of this study was to analyse, for the first time, the relationship between muscle performance-related genes and the risk of an increased body mass index (BMI) and muscle mass and a decrease in fat mass in professional football players after creatine supplementation. METHODS: For this longitudinal study, one hundred and sixty-one men's professional football players were recruited. The polymorphisms ACE I/D, ACTN3 c.1729C>T, AMPD1 c.34C>T, CKM c.*800A>G, and MLCK (c.49C>T and c.37885C>A) were genotyped using Single-Nucleotide Primer Extension (SNPE). To assess the combined impact of these six polymorphisms, a total genotype score (TGS) was calculated. The creatine supplementation protocol consisted of 20 g/day of creatine monohydrate for 5 days (loading dose) and 3-5 g/day for 7 weeks (maintenance dose). Anthropometric characteristics (body mass index (BMI), fat, and muscle mass) were recorded before and after the creatine supplementation protocol. Characteristics of non-contact muscle injuries during the 2022/2023 season were classified according to a consensus statement for injury recording. The results showed that the allelic frequencies of ACE and AMPD1 differed between responders and non-responders in muscle mass increase (all p < 0.05). Players with a TGS exceeding 54.16 a.u. had an odds ratio (OR) of 2.985 (95%CI: 1.560-5.711; p = 0.001) for muscle mass increase. By contrast, those with a TGS below 54.16 a.u. had an OR of 9.385 (95%CI: 4.535-19.425; p < 0.001) for suffering non-contact muscle injuries during the season. CONCLUSIONS: The increase in BMI and muscle mass in response to creatine supplementation in professional football players was influenced by a TGS derived from the combination of favourable genotypes linked to muscle performance. The CC genotype and C allele of AMPD1 were particularly associated with a higher likelihood of muscle mass increase under creatine supplementation in this group of professional football players.

Exercise-induced changes in intramuscular total creatine concentration measured with 1H magnetic resonance spectroscopy: A pilot study.

Total amount of creatine (Cr) and phosphocreatine, or total creatine (tCr), may have a significant impact on the performance of skeletal muscles. In sports such as bodybuilding, it is popular to take Cr supplements to maintain tCr level. However, no study has explored the quantitative relationship between exercise intensity and the induced change in muscle's tCr. In this well-controlled study, straight-leg plantar flexion with specific load and duration was performed by 10 healthy subjects inside an MRI scanner, immediately followed by 1H MR spectroscopy (MRS) for measuring tCr concentration in gastrocnemius. For repeatability assessment, the experiment was repeated for each subject on two different days. Across all the subjects, baseline tCr was 46.6 ± 2.4 mM, ranging from 40.6 to 50.1 mM; with exercise, tCr significantly decreased by 10.9% ± 1.0% with 6-lb load and 21.0% ± 1.3% with 12-lb load (p < 0.0001). Between two different days, baseline tCr, percentage decrease induced by exercise with a 6-lb and 12-lb load differed by 2.2% ± 2.3%, 11.7% ± 6.0% and 4.9% ± 3.2%, respectively. In conclusion, the proposed protocol of controlled exercise stimulation and MRS acquisition can reproducibly monitor tCr level and its exercise-induced change in skeletal muscles. The measured tCr level is sensitive to exercise intensity, so can be used to quantitatively assess muscle performance or fatigue.

Analysis of food supplements and sports foods consumption patterns among a sample of gym-goers in Portugal.

BACKGROUND: Gym-goers usually seek methods to improve performance, muscle gain, and overall health. One of the main strategies is including food supplements (FS) into their routine as aids to enhance their athletic capabilities and satisfy their nutritional needs. Thus, this study aimed to investigate and characterize the main FS and Sports Foods (SF) currently consumed, as well as the main reasons for their use and the source of advice in a group of gym-goers in the Lisbon Metropolitan Area (Portugal). METHODS: A cross-sectional study was conducted, including 303 gym-goers from Lisbon, Portugal, who were 133 women and 170 males (30.8 ± 12.9 years old). Face-to-face interviews were used by qualified researchers to gather data. RESULTS: Most of the interviewed athletes (71.95 %) took FS/SF, being men the main consumers. On average, 1.59 supplements were consumed per athlete. Logistic regression models indicated significant associations between age, gender, and motivations for gym attendance. While men and younger groups attended mainly for hypertrophy, women and older groups were focused on well-being. Protein (59.17 %) was the most used FS/SF, followed by creatine (41.28 %) and multivitamins (27.06 %). Men and younger individuals preferred protein and creatine, while older individuals focused more on specific vitamins and minerals. Women seemed to prefer L-carnitine and protein yogurts. Main sources of information included the internet, friends, and dietitians with notable gender and age-based preferences. Online stores were the main place of purchase. Monthly expenditures on FS/SF were not significantly affected by age or gender, but motivations for use had an influence. CONCLUSION: Most of the athletes interviewed took FS/SF, being men the major consumers. Protein was the principal FS/SF used, with online stores being the main place of purchase and the internet the primary source of information. Age and gender were key factors in adopted training, in the FS/SF chosen, and in the source of information selected. It is crucial that health professionals take primary responsibility for providing this guidance.

Creatine Improves Total Sleep Duration Following Resistance Training Days versus Non-Resistance Training Days among Naturally Menstruating Females.

Females historically experience sleep disturbances and overall poor sleep compared to males. Creatine has been proposed to impact sleep; however, the effects are not well known. The purpose of this study was to examine the effects of creatine supplementation on sleep among naturally menstruating females. Twenty-one participants completed a double-blind, randomized controlled trial in which they consumed 5 g creatine + 5 g maltodextrin or placebo, 10 g maltodextrin, daily for 6 weeks. Participants completed resistance training 2x/week using the TONAL® (Tonal Systems Inc., San Francisco, CA, USA) at-home gym. Pre- and post-testing assessed body composition, Pittsburgh Sleep Quality Index (PSQI), dietary intake, and muscular strength. Sleep was assessed nightly using an OURA® (Oulu, Finland) ring. Compared to the placebo group, those consuming creatine experienced significant increases in total sleep on training days (p = 0.013). No significant changes in chronic sleep and PSQI (pre-post) were observed. There was a significant increase in TONAL® strength score over time (p < 0.001), with no between-group differences. Participants reduced their total calorie (kcal) (p = 0.039), protein (g/kg) (p = 0.009), carbohydrate (g/kg) (p = 0.023), and fat (g) (p = 0.036) intake over time. Creatine supplementation increases sleep duration on resistance training days in naturally menstruating females.

Creatine monohydrate use is prospectively associated with muscle dysmorphia symptomatology.

This study aimed to determine the prospective association between creatine monohydrate use and muscle dysmorphia symptomatology among adolescents and young adults in Canada. Data from 912 adolescents and young adults from the Canadian Study of Adolescent Health Behaviors were analyzed. Creatine monohydrate use in the past 12 months was assessed at Wave 1, and muscle dysmorphia symptomatology was measured using the Muscle Dysmorphic Disorder Inventory (MDDI) at Wave 1 and Wave 2. The prospective associations between creatine monohydrate use and the MDDI total score and subscale scores were determined using linear regression analyses. Regression analyses controlled for relevant demographic identifiers, prior substance use, and the corresponding Wave 1 MDDI variable. Creatine monohydrate use at Wave 1 was prospectively associated with both total muscle dysmorphia symptomatology (B 1.34, 95 % CI 0.27, 2.42) and greater Appearance Intolerance (B 0.52, 95 % CI 0.02, 1.03) at Wave 2. Importantly, these findings were independent of prior muscle dysmorphia symptomatology, lifetime anabolic-androgenic steroid use, lifetime cigarette use, and frequency of alcohol use. Creatine monohydrate is commonly used among adolescents and young adults. Findings from this study are among the first to document that creatine monohydrate use may be a risk factor for the development of muscle dysmorphia symptomatology among adolescents and young adults. Health and mental health care professionals may consider assessing for both creatine monohydrate use and muscle dysmorphia symptomatology among adolescents and young adults.

Dietary Supplementation on Physical Performance and Recovery in Active-Duty Military Personnel: A Systematic Review of Randomized and Quasi-Experimental Controlled Trials.

BACKGROUND: Warfighters, often called tactical athletes, seek dietary supplementation to enhance training and recovery. Roughly 69% of active-duty US military personnel have reported consuming dietary supplements. The objective of this systematic review was to examine the impact of dietary supplements on muscle-related physical performance and recovery in active-duty military personnel. METHODS: Randomized controlled trials and quasi-experimental controlled trials of oral dietary supplementation in active-duty military members were examined. A protocol was registered (PROSPERO CRD42023401472), and a systematic search of MEDLINE and CINAHL was undertaken. Inclusion criteria consisted of studies published between 1990-2023 with outcomes of muscle performance and recovery among active-duty military populations. The risk of bias was assessed with the McMaster University Guidelines and Critical Review Form for Quantitative Studies. RESULTS: Sixteen studies were included. Four were conducted on protein or carbohydrate; four on beta-alanine alone, creatine alone, or in combination; two on mixed nutritional supplements; two on probiotics alone or in combination with beta hydroxy-beta methylbutyrate calcium; and four on phytonutrient extracts including oregano, beetroot juice, quercetin, and resveratrol. Ten examined outcomes related to physical performance, and six on outcomes of injury or recovery. Overall, protein, carbohydrate, beta-alanine, creatine, and beetroot juice modestly improved performance, while quercetin did not. Protein, carbohydrates, beta-alanine, probiotics, and oregano reduced markers of inflammation, while resveratrol did not. CONCLUSIONS: Nutrition supplementation may have small benefits on muscle performance and recovery in warfighters. However, there are significant limitations in interpretation due to the largely inconsistent evidence of ingredients and comparable outcomes. Thus, there is inadequate practical evidence to suggest how dietary supplementation may affect field performance.

Altered brain metabolites in male nonhuman primate offspring exposed to maternal immune activation.

Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (both p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.

Non-invasive mapping of brown adipose tissue activity with magnetic resonance imaging.

Thermogenic brown adipose tissue (BAT) has a positive impact on whole-body metabolism. However, in vivo mapping of BAT activity typically relies on techniques involving ionizing radiation, such as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) and computed tomography (CT). Here we report a noninvasive metabolic magnetic resonance imaging (MRI) approach based on creatine chemical exchange saturation transfer (Cr-CEST) contrast to assess in vivo BAT activity in rodents and humans. In male rats, a single dose of the ß3-adrenoceptor agonist (CL 316,243) or norepinephrine, as well as cold exposure, triggered a robust elevation of the Cr-CEST MRI signal, which was consistent with the [18F]FDG PET and CT data and 1H nuclear magnetic resonance measurements of creatine concentration in BAT. We further show that Cr-CEST MRI detects cold-stimulated BAT activation in humans (both males and females) using a 3T clinical scanner, with data-matching results from [18F]FDG PET and CT measurements. This study establishes Cr-CEST MRI as a promising noninvasive and radiation-free approach for in vivo mapping of BAT activity.

Effects of acute creatine supplementation on cardiac and vascular responses in older men; a randomized controlled trial.

BACKGROUND AND AIMS: In the recent years creatine has been shown promising results in patients with neurodegenerative diseases, myopathies and dystrophies. Cardiovascular diseases could be another pathology that can benefit from creatine supplementation, considering the influence on the risk factors associated with the development of cardiovascular diseases including reduction in chronic inflammation, and improved control of hyperglycemia and dyslipidemia The aim of the present study was to investigate the impact of short-term creatine supplementation on cardiac and vascular health in older adults. METHODS: Males between the ages of 55-80 were randomly assigned to three groups: creatine, placebo and control. Creatine or placebo was provided for 7-day supplementation, at a dose of 20 g/day. Testing was performed at the same time of the day at baseline and on the eighth day. Vascular responses were assessed using an arterial pulse wave velocity equipment, while cardiac assessment was performed using an impedance cardiography device. RESULTS: The placebo group was older (71.1 ± 8.2 yr) compared to creatine (61.4 ± 5.2 yr) and control (62.5 ± 7.1 yr). Cardio-ankle vascular index improved just in the creatine group (8.7 ± 0.5 to 8.2 ± 0.5, p = 0.03). While the upstroke time of the placebo and control groups did not change after 7 days, the creatine group had a nonsignificant reduction, 178.9 ± 26.5 ms to 158.4 ± 28.6 ms, p = 0.07. Similar tendency was seen with the systolic blood pressures, while the placebo and control did not change, the creatine group showed nonsignificant improvement, especially on the right, 144.0 ± 12.7 mmHg to 136.1 ± 13.4 mmHg, p = 0.08. All three groups had similar responses in stroke volume (p = 0.61), contractility index (p = 0.64) and ejection fraction (p = 0.72). CONCLUSIONS: In older adults, acute creatine supplementation can positively affect vascular parameters of arterial stiffness and atherosclerosis. Creatine supplementation has the potential to serve as a potent adjuvant in the management of CVD for older adults. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; ID: NCT05329480.

Creatine supplementation protocols with or without training interventions on body composition: a GRADE-assessed systematic review and dose-response meta-analysis.

BACKGROUND: Despite the robust evidence demonstrating positive effects from creatine supplementation (primarily when associated with resistance training) on measures of body composition, there is a lack of a comprehensive evaluation regarding the influence of creatine protocol parameters (including dose and form) on body mass and estimates of fat-free and fat mass. METHODS: Randomized controlled trials (RCTs) evaluating the effect of creatine supplementation on body composition were included. Electronic databases, including PubMed, Web of Science, and Scopus were searched up to July 2023. Heterogeneity tests were performed. Random effect models were assessed based on the heterogeneity tests, and pooled data were examined to determine the weighted mean difference (WMD) with a 95% confidence interval (CI). RESULTS: From 4831 initial records, a total of 143 studies met the inclusion criteria. Creatine supplementation increased body mass (WMD: 0.86 kg; 95% CI: 0.76 to 0.96, I2 = 0%) and fat-free mass (WMD: 0.82 kg; 95% CI: 0.57 to 1.06, I2 = 0%) while reducing body fat percentage (WMD: -0.28 %; 95% CI: -0.47 to -0.09; I2 = 0%). Studies that incorporated a maintenance dose of creatine or performed resistance training in conjunction with supplementation had greater effects on body composition. CONCLUSION: Creatine supplementation has a small effect on body mass and estimates of fat-free mass and body fat percentage. These findings were more robust when combined with resistance training.

Development of a functional beige fat cell line uncovers independent subclasses of cells expressing UCP1 and the futile creatine cycle.

Although uncoupling protein 1 (UCP1) is established as a major contributor to adipose thermogenesis, recent data have illustrated an important role for alternative pathways, particularly the futile creatine cycle (FCC). How these pathways co-exist in cells and tissues has not been explored. Beige cell adipogenesis occurs in vivo but has been difficult to model in vitro; here, we describe the development of a murine beige cell line that executes a robust respiratory response, including uncoupled respiration and the FCC. The key FCC enzyme, tissue-nonspecific alkaline phosphatase (TNAP), is localized almost exclusively to mitochondria in these cells. Surprisingly, single-cell cloning from this cell line shows that cells with the highest levels of UCP1 express little TNAP, and cells with the highest expression of TNAP express little UCP1. Immunofluorescence analysis of subcutaneous fat from cold-exposed mice confirms that the highest levels of these critical thermogenic components are expressed in distinct fat cell populations.

Spectrophotometric and chromatographic analysis of creatine:creatinine crystals in urine.

Creatinine is the end product of the catabolism of creatine and creatine phosphate. Creatine phosphate serves as a reservoir of high-energy phosphate, especially in skeletal and cardiac muscle. Besides typical known changes in serum and urinary creatinine concentrations, rare cases associated with changes in serum and urinary creatine levels have been described in the literature in humans. These cases are mostly linked to an excessive intake of creatine ethyl ester or creatine monohydrate, often resulting in increased urine creatinine concentrations. In addition, it is known that at such elevated creatinine concentrations, creatinine crystallisation may occur in the urine. Analysis of crystals and urinary concrements, often of heterogenous chemical composition, may provide diagnostic and therapeutic hints to the benefit of the patient. The aim of the present work was to analyze urine crystals of unclear composition with microscopic and spectroscopic techniques. On routine microscopic analysis of urine, a preliminary suspicion of uric acid or creatinine crystals was expressed. The crystals were of a cuboid shape and showed polarization effects in microscopy. The dried urine sample was whitish-orange in colour, odourless and dissolved well in water. Protein concentration in dry weight (DW) urine was about 0.3 mg/mg. The measured zinc content in the studied sample was approximately 660 µg/g DW sample and copper content was approximately 64 µg/g DW sample. A lead signal of around 10 µg/g DW sample was also observed. UV-Vis analysis showed a maximum creatine peak around 220 nm, compatible with the spectrum of creatinine with a maximum peak of 230 nm. Using HPLC technique, an extreme high ratio of creatine to creatinine of about 38 was measured, which led to the conclusion of the occurrence of rare creatine crystals in urine.

Short Communication: The effect of in ovo creatine monohydrate on early pen use activity in chicks.

First-week survival and egg hatchability are lower in chicks from younger broiler breeder hen flocks. Creatine is a naturally occurring compound synthesised from the amino acid arginine or obtained from the diet and is important in the storage and transport of energy. Previous research found an improvement in the hatch rate but no posthatch performance improvements when fertile eggs from young breeder hens were injected with creatine monohydrate (CrM) on embryonic day 14. This pilot study aimed to further investigate the possibility of early posthatch improvements by examining the activity of chicks during the 1st week posthatch. Behaviours were broadly classified as active or inactive, the pen was split into three areas, and the amount of time spent in the heat lamp, feed hopper, or drinker line areas was recorded. Chicks given in ovo CrM spent less time in the heat lamp area over the whole 7 days compared to saline (t = 2.352, P = 0.021) and control groups (t = 3.336, P = 0.003) and more time in the feed hopper area during the first 4 days compared to the control group (t = 2.174, P = 0.033). This finding suggests that creatine may improve energy reserves in young chicks allowing them to spend more time away from the heat lamp.